2-saccharinylmethyl heterocyclic carboxylates useful as proteolytic enzyme inhibitors and compositions and method of use thereof

ABSTRACT

4-R 4  -R 5  -2-Saccharinylmethyl heterocyclic carboxylates, useful in the treatment of degenerative diseases, are prepared by reacting a 4-R 4  -R 5  -2-halomethylsaccharin with either a heterocyclic carboxylic acid in the presence of an acid-acceptor or the alkali metal salt of a heterocyclic carboxylic acid.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of our application Ser. No. 08/287,681,filed on Aug. 9, 1994, now U.S. Pat. No. 5,489,062 which in turn is adivision of our prior application Ser. No. 08/109,411, filed on Aug. 19,1993, now U.S. Pat. No. 5,376,653 which in turn is a continuation of ourprior Application Ser. No. 07/816,621, filed on Dec. 30, 1991, nowabandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel 2-saccharinylmethyl heterocycliccarboxylates, which inhibit the enzymatic activity of proteolyticenzymes, to compositions containing the same, to the method of usethereof in the treatment of degenerative diseases and to processes fortheir preparation.

2. Information Disclosure Statement

The inhibition of proteolytic enzymes by nontoxic reagents is useful inthe treatment of degenerative disorders, such as emphysema, rheumatoidarthritis and pancreatitis, in which proteolysis is a substantiveelement.

Protease inhibitors are widely utilized in biomedical research. Serineproteases are the most widely distributed class of proteolytic enzymes.Some serine proteases are characterized as chymotrypsin-like orelastase-like based upon their substrate specificity.

Chymotrypsin and chymotrypsin-like enzymes normally cleave peptide bondsin proteins at a site at which the amino acid residue on the carboxylside is typically Trp, Tyr, Phe, Met, Leu or another amino acid residuewhich contains aromatic or large alkyl side chains.

Elastase and elastase-like enzymes normally cleave peptide bonds at asite at which the amino acid residue on the carboxyl side of the bond istypically Ala, Val, Ser, Leu or other similar, smaller amino acids.

Both chymotrypsin-like and elastase-like enzymes are found inleukocytes, mast cells and pancreatic juice in higher organisms, and aresecreted by many types of bacteria, yeast and parasites.

Japanese Patent Publication 72/00419 discloses a number of2-RZ-methylsaccharins, stated to have strong activity against riceblast, rice sheath blight, rice helminthosporium leaf spot and ricebacterial leaf blight disease, wherein RZ is lower-alkoxy, butoxyethoxy,ethylthioethoxy, di-lower-alkylaminoethoxy, ethylthio, 2-chloroethoxy,1-(2-propenyloxy), 1-(2-propynyloxy), 2-saccharinylmethoxy, phenoxy (orphenoxy substituted by chlorine, methyl, nitro or methylthio),phenylthio, chlorophenylthio, benzylthio (or chlorobenzylthio), acetoxy,dichloroacetoxy, benzoyloxy (or benzoyloxy substituted by chlorine ornitro), acetylthio, dichloroacetyloxy, chlorobenzoylthio, methyl orethylcarbamyloxy, dimethylcarbamyloxy, phenylcarbamyloxy,ethylcarbamylthio, phenylcarbamylthio, dimethylthioylcarbamothioyl,ethylthiothioylthio, ethoxycarbonylthio, ethoxythioylthio andethylthiocarbonylthio.

Sunkel et al., J. Med. Chem., 31, 1886-1890 (1988) disclose a series of2-saccharinyl-lower-alkyl-1,4-dihydropyridine-3-carboxylates havingplatelet aggregation inhibitory and anti-thrombotic activities.

Chen, U.S. Pat. No. 4,263,393, patented Apr. 21, 1981, discloses various2-aroylmethylsaccharins useful as "photographic elements and filmunits".

Mulvey et al. U.S. Pat. No. 4,195,023, patented Mar. 25, 1980, disclosesR₁ -2-R₂ CO-1,2-benzisothiazol-3-ones, where R₁ is halogen, alkoxy,alkylamino, dialkylamino, alkoxycarbonyl, amino, nitro or hydrogen inthe benzenoid ring and R₂ is hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, halophenyl, heteroaryl or substituted heteroaryl, and R₁-2-A-CO saccharins, where R₁ has the same meanings as the benzenoid ringsubstituents in the 1,2-benzisothiazol-3-ones and A is alkyl, alkenyl,alkynyl, cycloalkyl, fluorophenyl, heteroaryl or substituted-heteroaryl.The compounds are said to have elastase inhibitory activity and to beuseful in the treatment of emphysema.

Zimmerman et al., J. Biol. Chem., 255(20), 9848-9851 (1980) discloseN-acylsaccharins, where the acyl group is furoyl, thenoyl, benzoyl,cyclopropanoyl, ethylbutyryl and acryloyl, having serine proteaseinhibitory activity.

Chiyomaru et al., Chemical Abstracts 81:22249n, disclose 4-methylphenyl2-saccharinyl-carboxylate which is said to have bactericidal andfungicidal activities.

Several classes of compounds are known to be serine protease inhibitors.For example Powers U.S. Pat. No. 4,659,855 discloses arylsulfonylfluoride derivatives useful as elastase inhibitors. Doherty et al. U.S.Pat. Nos. 4,547,371 and 4,623,645 disclose cephalosporin sulfones andsulfoxides, respectively, which are stated to be potent elastaseinhibitors useful in the treatment of inflammatory conditions,especially arthritis and emphysema.

Teshima et al., J. Biol. Chem., 257(9) , 5085-5091 (1982) report theresults of studies on serine proteases (human leukocyte elastase,porcine pancreatic elastase, cathepsin G and bovine chymotrypsinA.sub.α) with 4-nitrophenylesters and thioesters ofN-trifluoroacetylanthranilates, 2-substituted-4H-3,1-benzoxazin-4-ones,2-substituted-4-quinazolinones and 2-substituted-4-chloroquinazolines.

Cha, Blochem. Pharmacol., 24, 2177-2185 (1975) discusses kineticapproaches to the study of the binding of inhibitors to macromolecules,such as enzymes, and methods for determination of such parameters as theinhibition constants, reaction rates and bound and unbound enzymeconcentrations.

Jones et al., U.S. Pat. No. 4,276,298 discloses2-R-1,2-benzisothiazolinone-1,1-dioxides, where R is phenyl substitutedby fluoro, dinitro, trifluoromethyl, cyano, alkoxycarbonyl,alkylcarbonyl, carboxyl, carbamoyl, alkylacylamino, alkylsulfonyl,N,N-dialkylsulfamoyl, trifluoromethoxy, trifluoromethylthio,trifluoromethylsulfonyl and trifluoromethylsulfinyl, or pyridylsubstituted the same as R when R is phenyl except that pyridyl may alsobe mononitro substituted. The compounds are said to have protease enzymeinhibitory activity, especially elastase inhibitory activity, and to beuseful in the treatment of emphysema, rheumatoid arthritis "and otherinflammatory diseases".

Powers et al., Biochem., 24, 2048-2058 (1985) discloses studies of theinhibitions of four chymotrypsin-like enzymes, cathepsin G, rat mastcell proteases I and II, human skin chymase and chymotrypsin A_(a), byN-furoylsaccharin and N-(2,4-dicyanophenyl)saccharin.

Svoboda et al., Coll. Czech. Chem. Commun., 51, 1133-1139 (1986)disclose the preparation of4-hydroxy-2H-1,2-benzothiazine-3-carboxylates by intramolecularDieckmann condensation of 2H-1,2-benzisothiazol-3-one-2-acetate-1,1-dioxide esters.

Reczek et al. U.S. Pat. Nos. 4,350,752 and 4,363,865 and Vanmeter et al.U.S. Pat. No. 4,410,618 relate to photographic reagents (Reczek U.S.Pat. No. 4,350,752 and Vanmeter et al.) and photographic dyes (ReczekU.S. Pat. No. 4,363,865) and disclose various 2-substituted-saccharinsuseful for such applications, for example "photographic reagents" boundthrough a heteroatom to an "imidomethyl blocking" group (Reczek U.S.Pat. No. 4,350,752) , "carrier-diffusible photographic dyes" bound tothe nitrogen atom of an imide through a 1,1-alkylene group (Reczek U.S.Pat. No. 4,363,865) and N-acylmethylimides which are described as"blocked photographic reagents" and which have a "residue of an organicphotographic reagent containing a hetero atom through which it is boundto the blocking group" (Vanmeter).

Freed et al., U.S. Pat. No. 3,314,960 discloses2-(1,1,3-trioxo-1,2-benzisothiazol-2-yl)glutarimides which are stated tobe useful as sedatives.

2-Chloromethylsaccharin is disclosed in French Patent 1,451,417 as anintermediate for the preparation of N-methylsaccharind,1-trans-chrysanthemate, useful as an insecticide, and Lo U.S. Pat. No.3,002,884 discloses 2-chloro, 2-bromo and 2-iodomethylsaccharins, usefulas fungicidal agents.

Dunlap et al. PCT application WO 90/13549, published Nov. 15, 1990,discloses a series of 2-substituted saccharin derivatives useful asproteolytic enzyme inhibitors.

SUMMARY OF THE INVENTION

In a composition of matter aspect, this invention relates to 4-R⁴ -R⁵-2-saccharinylmethyl heterocyclic carboxylates and4,5,6,7-tetrahydro-2-saccharinylmethyl heterocyclic carboxylates whichhave protease enzyme inhibitory activity and which are useful in thetreatment of degenerative diseases.

In a composition aspect, the invention relates to compositions for thetreatment of degenerative diseases which comprise a pharmaceuticalcarrier and an effective proteolytic enzyme inhibiting amount of a 4-R⁴-R⁵ -2-saccharinylmethyl heterocyclic carboxylate or a4,5,6,7-tetrahydro-2-saccharinylmethyl heterocyclic carboxylate.

In a method aspect, the invention relates to a method of use of said2-saccharinylmethyl heterocyclic carboxylates in the treatment ofdegenerative diseases which comprises administering to a patient in needof such treatment a medicament containing an effective proteolyticenzyme inhibiting amount of a 4-R⁴ -R⁵ -2-saccharinylmethyl heterocycliccarboxylate or a 4,5,6,7-tetrahydro-2-saccharinylmethyl heterocycliccarboxylate.

In process aspects, the invention relates to processes for thepreparation of said 4-R⁴ -R⁵ -2-saccharinylmethyl heterocycliccarboxylates and 4,5,6,7-tetrahydro-2-saccharinylmethyl heterocycliccarboxylates which comprises reacting (1) a 2-halomethylsaccharin with aheterocyclic carboxylic acid in the presence of an acid-acceptor, or (2)reacting an alkali metal salt of the appropriate acid with theappropriate halomethyl species.

DETAILED DESCRIPTION INCLUSIVE OF THE PREFERRED EMBODIMENTS

More specifically this invention relates to 4-R⁴ -R⁵-2-saccharinylmethyl heterocyclic carboxylates having the formula:##STR1## wherein:

Het is a 5- or 6-membered monocyclic heterocycle, or a 9- or 10-memberedbicyclic heterocycle containing from 1 to 2 heteroatoms selected fromoxygen, nitrogen and sulfur, or said heterocycles substituted by fromone to three, the same or different, members of the group consisting oflower-alkyl, perfluorolower-alkyl, lower-alkoxy, oxo, phenyl, halogen,and --O--(C₂ -C₁₀ alkylene)-N═B where N═B is dilower-alkylamino,1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl, or4-lower-alkyl-1-piperazinyl;

R⁴ is hydrogen, halogen, lower-alkyl, perfluorolower-alkyl,perchlorolower-alkyl, lower-alkenyl, lower-alkynyl, cyano, carboxamido,amino, lower-alkylamino, dilower-alkylamino, lower-alkoxy, benzyloxy,lower-alkoxycarbonyl, hydroxy or phenyl; and

R⁵ is hydrogen or from one to two substituents in any of the 5-, 6- or7-positions selected from halogen, cyano, nitro, N═B',lower-alkyl-2-pyrrolyl, lower-alkylsulfonyl-amino,poly-fluorolower-alkylsulfonylamino, polychlorolower-alkylsulfonylamino,aminosulfonyl, lower-alkyl, polyfluoro-lower-alkyl,poly-chlorolower-alkyl, cycloalkyl, lower-alkoxy, hydroxy, carboxy,carboxamido, hydroxylower-alkyl, methylenedioxy, cycloalkyloxy, formyl,aminomethyl, polyfluorolower-alkylsulfonyl,polychloro-lower-alkylsulfonyl, lower-alkylsulfonylaminosulfonyl,di(lower-alkyl)phosphonoxy, lower-alkoxy-poly-lower-alkyleneoxy,hydroxy-lower-alkoxy, polyhydroxy-alkoxy, or acetal or ketal thereof,polyalkoxy-alkoxy, --SR, --SOR, --SO₂ R, --OCOR, --O--(C₁ -C₁₀alkylene)--COOR, --O--(C₂ -C₁₀ alkylene)-N═B' where R is lower-alkyl,phenyl, benzyl or naphthyl, or phenyl or naphthyl substituted by fromone to two substituents selected from lower-alkyl, lower-alkoxy orhalogen and where N═B' is amino, lower-alkylamino, dilower-alkylamino,1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl,1-piperazinyl, 4-lower-alkyl-1-piperazinyl, 4-benzyl-1-piperazinyl,1-imidazolyl or (carboxy-lower-alkyl)amino; or R⁵ is a 5- or 6-memberedsaturated ring fused to the saccharin ring at the 5,6 or 6,7 positions,said ring containing two heteroatoms chosen from the group consisting ofnitrogen, oxygen and sulfur or a methylated derivative of said ring;

or acid-addition salts of basic members thereof or base-addition saltsof acidic members thereof, with the proviso that, when R⁴ and R⁵ areboth hydrogen, Het cannot be a dihydropyridine.

Preferred compounds of formula I above are those wherein:

R⁴ is hydrogen, halogen, lower-alkyl or lower-alkoxy and R⁵ is hydrogen,lower-alkoxy, methylenedioxy, cycloalkyloxy, hydroxylower-alkoxy,polyhydroxy-alkoxy or acetal or ketal thereof, polyalkoxy-alkoxy,--O--(C₁ -C₁₀ alkylene) --COOR, or --O--(C₂ -C₁₀ alkylene)-N═B'.

Particularly preferred compounds of formula I above are those wherein:

Het is 4-pyridinyl, 3,5-dichloro-4-pyridinyl, 2,4-dimethyl-3-pyridinyl,or 3,5-dichloro-2-[O-(C₂ -C₁₀ alkylene)-N═B]-4-pyridinyl;

R⁴ is hydrogen or lower alkyl; and

R⁵ is hydrogen or lower alkoxy.

Other preferred compounds of formula I above are those wherein:

Het is thienyl, methylthienyl or chlorothienyl;

R⁴ is lower alkyl; and

R⁵ is lower alkoxy.

The invention also relates to 4,5,6,7-tetrahydro-2-saccharinylmethylheterocyclic carboxylates of formula VI ##STR2## wherein R^(4a) ishydrogen, lower-alkyl or phenyl; R⁶ is hydrogen or primary lower-alkylor R^(4a) and R⁶ together form a spirocyclopropyl ring; R⁷ is hydrogenor lower-alkoxy, and Het is as defined for formula I.

The tetrahydrosaccharin may contain a 4,7-alkylene bridge and hence theinvention also relates to compounds of the formula ##STR3## wherein A ismethylene, ethylene or dimethylmethylene and Het is as defined forformula I,

It should be understood that the compounds having the general structuralformula I are usually named in the chemical literature as1,2-benzisothiazol-3 (2H) -one 1,1-dioxides. However, for the sake ofbrevity, such compounds are frequently named as saccharin derivatives,and that nomenclature will be used hereinafter in describing thecompounds of the invention and their biological properties.

As used herein the terms lower-alkyl, lower-alkoxy and lower-alkane meanmonovalent aliphatic radicals, including branched chain radicals, offrom one to ten carbon atoms. Thus the lower-alkyl (or lower-alkane)moiety of such groups include, for example, methyl, ethyl, propyl,isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 2-methyl-3-butyl,1-methylbutyl, 2-methylbutyl, neopentyl, n-hexyl, 1-methylpentyl,3-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 2-hexyl, 3-hexyl,1,1,3,3-tetramethylpentyl, 1,1-dimethyloctyl and the like.

As used herein, the term C₁ -C₁₀ alkylene means divalent, saturatedradicals, including branched chain radicals, of from one to ten carbonatoms and having their free valences on the same or different carbonatoms and thus includes methylene, 1,2-ethylene, ethylidene,1,3-propylene, proylidene and the like.

As used herein, the term lower-alkoxy-poly-lower-alkyleneoxy means suchradicals in which lower-alkoxy has the meaning given above, poly means 2to 4, and lower-alkylene in lower-alkyleneoxy means divalent saturatedradicals, including branched radicals, of from two to five carbon atoms.The term thus includes CH₃ (OCH₂ CH₂)p--O--, CH₃ CH₂ [OCH₂CH(CH₃)]p--O--, where p═2-4, and the like.

As used herein, hydroxy-lower-alkoxy means lower-alkoxy as defined abovesubstituted by an hydroxy group other than on the C-1 carbon atom andthus includes 2-hydroxyethoxy and the like.

As used herein, the term polyhydroxy-alkoxy means such a group whereinalkoxy is a monovalent aliphatic radical of from two to five carbonatoms substituted by from two to four hydroxy groups none of which areattached to the same or the C-1 carbon atom and thus includes2,3-dihydroxypropoxy, 2,3,4,5-tetrahydroxypentoxy and the like.

As used herein, the term polyalkoxy-alkoxy means monovalent aliphaticalkoxy radicals of from three to five carbon atoms substituted by fromtwo to four methoxy or ethoxy groups none of which are attached to thesame or the C-1 carbon atom.

As used herein the term halogen (or halo) means fluorine, chlorine,bromine or iodine.

As used herein the terms lower-alkenyl and lower-alkynyl meanmonovalent, unsaturated radicals, including branched chain radicals, offrom two to ten carbon atoms and thus include 1-ethenyl, 1-(2-propenyl),1-(2-butenyl), 1-(1-methyl-2-propenyl), 1-(4-methyl-2-pentenyl),4,4,6-trimethyl-2-heptenyl, 1-ethynyl, 1-(2-propynyl), 1-(2-butynyl),1-(1-methyl-2-propynyl), 1-(4-methyl-2-pentynyl), and the like.

As used herein, the term C₂ -C₁₀ alkylene means divalent, saturatedradicals, including branched chain radicals, of from two to ten carbonatoms and having their free valences on different carbon atoms and thusincludes 1,2-ethylene, 1,3-propylene, 1,4-butylene,1-methyl-1,2-ethylene, 1,8-octylene and the like.

As used herein cycloalkyl means C₃ through C₇ saturated monocyclichydrocarbon residues and thus includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

The compounds of the present invention inhibit the activity of serineproteases, specifically human leukocyte elastase and thechymotrypsin-like enzymes, and are thus useful in the treatment ofdegenerative disease conditions such as emphysema, rheumatoid arthritis,pancreatitis, cystic fibrosis, chronic bronchitis, adult respiratorydistress syndrome, inflammatory bowel disease, psoriasis, bullouspemphigoid and alpha-1-antitrypsin deficiency.

The compounds of formula I and formula VI can be prepared by reaction ofa 2-halomethylsaccharin or 2-halomethyl-4,5,6,7-tetrahydrosaccharin withan appropriate heterocyclic carboxylic acid, HetCOOH, in the presence ofan acid-acceptor, such as an alkali metal carbonate or atrilower-alkylamine. Alternatively an alkali metal salt, especially acesium salt, of the heterocyclic carboxylic acid, HetCOO⁻⁺ M, (preparedby reaction of the acid with an alkali metal carbonate) can be reactedwith the 2-halomethyl compound. These reactions can also be optionallyrun in the presence of tetrabutylammonium bromide (TBAB). Thesereactions can be carried out in an inert organic solvent such as xylene,acetonitrile, methylene dichloride, N-methyl-2-pyrrolidinone, ordimethylformamide (DMF) at a temperature in the range from ambient up tothe boiling point of the solvent used. The reactions are illustrated asfollows where X is chloro, bromo or iodo. ##STR4##

The 4-R⁴ -R⁵ -2-halomethylsaccharins required for the preparation of thecompounds of formula I are prepared by the methods described by D'Alelioet al., J. Macromol. Sci-Chem., A3(5), 941 (1969) and Saari et al., J.Het. Chem., 23, 1253 (1986) as shown below where Alk is lower alkyl.##STR5## In the method described by Saari, an ester of an appropriateanthranilic acid is prepared by conventional means from the substitutedanthranilic acid and the ester diazotized. The diazonium salt is thenreacted with sulfur dioxide and cuptic chloride to produce a sulfonylchloride which is then reacted with concentrated ammonium hydroxide toproduce the substituted saccharin derivatives of formula II. The latter,on reaction with formaldehyde in a lower-alkanol solvent, affords the4-R⁴ -R⁵ -2-hydroxymethylsaccharins of formula III, which, on reactionwith a thionyl halide or a phosphorus trihalide, afford thecorresponding 4-R⁴ -R⁵ -2-halomethylsaccharin derivatives of formula IV.

The 4-R⁴ -R⁵ -2-halomethylsaccharins of formula IV, where R⁴, R⁵ and Xhave the meanings given above, can also be prepared by reaction of acorresponding 4-R⁴ -R⁵ -2-phenyl-thiomethyl-saccharin with a sulfurylhalide in an inert organic solvent, for example methylene dichloride(MDC), ethylene dichloride (EDC) or carbon tetrachloride, at atemperature from around 0° C. to around 30° C. The 4-R⁴ -R⁵-2-phenylthiomethylsaccharins are in turn prepared by reaction of a 4-R⁴-R⁵ -saccharin of formula II with a halomethyl phenyl sulfide in aninert organic solvent, such as toluene, xylene, DMF or MDC at atemperature in the range from ambient up to the boiling point of thesolvent used. The reaction can be carried out by reaction of thehalomethyl phenyl sulfide with either the thallium salt of the saccharinderivative of formula II (prepared by reaction of the saccharinderivative with a thallium lower-alkoxide in a lower-alkanol); or with adi-lower-alkyl ammonium salt of the saccharin derivatives (prepared asdescribed below) in the presence of a tetra-lower-alkyl ammonium halide,such as tetrabutyl ammonium bromide (hereinafter TBAB); or with thesaccharin derivative of formula II per se in the presence of atetralower-alkyl ammonium halide; or with the saccharin derivative offormula II per se in the presence of a tetralower-alkyl ammonium halideand an alkali metal lower-alkoxide, such as potassium t-butoxide.

The saccharins of formula II may also be converted to the chloromethylsaccharins of formula IV, wherein X is Cl, in one step by reaction withan excess of formaldehyde or a formaldehyde equivalent, such asparaformaldehyde or 1,3,5-trioxane, and a chlorosilane, preferablychlorotrimethylsilane in the presence of a Lewis acid, preferably acatalytic amount of stannic chloride in an inert solvent, preferably1,2-dichloroethane (ethylene dichloride, EDC).

It will be appreciated that all of the conversions of the saccharins IIto the 2-chloromethyl saccharins IV are equally applicable to theconversion of tetrahydrosaccharins VII to 2-chloromethyltetrahydrosaccharins VIII. ##STR6##

The compounds of formula II can also be prepared by reaction of a 2-R⁴-R⁵ -N,N-di-lower-alkylbenzamide of formula V with one molar equivalentof a lower-alkyl alkali metal, such as a lower-alkyl lithium, optionallyin the presence of a tetralower-alkylethylenediamine, in an inertorganic solvent, for example THF, and reaction of the resulting alkalimetal salt either with sulfur dioxide at a temperature in the range from-50° C. to -80° C. followed by reaction of the resulting alkali metalsulfinate with hydroxylamine-O-sulfonic acid in the presence of base, orwith a sulfuryl halide followed by ammonia. When the sulfurdioxide-hydroxylamine-O-sulfonic acid route is used, it is particularlyadvantageous to neutralize the hydroxylamine-O-sulfonic acid with oneequivalent of sodium hydroxide prior to addition of the alkali metalsulfinate. The resulting 2-R⁴ -R⁵-6-aminosulfonyl-N,N-dilower-alkylbenzamide is thereafter heated in anacid medium to effect cyclization of the latter to produce thedilower-alkyl ammonium salt of the desired 4-R⁴ -R⁵ -saccharin offormula II, which can be used as such in the subsequent reaction or, ifdesired, can be hydrolyzed in dilute acid and the free saccharinisolated. It is preferred to carry out the cyclization in refluxingglacial acetic acid. The method is illustrated as follows where R⁴, R⁵and Alk have the meanings given above. ##STR7##

The compounds of formula II where R⁴ is either primary or secondarylower-alkyl, and which are useful as intermediates for the preparationof the compounds of formula I as described above, are prepared by one ofthe following methods. The compounds of formula II where R⁴ is primarylower-alkyl are prepared by reacting a 4-methyl-R⁵ -saccharin (formulaII, R⁴ is CH₃) with two molar equivalents of a lower-alkyl lithium in aninert organic solvent, for example THF, and reacting the resultinglithium salt with one molar equivalent of a lower-alkyl halide, bothreactions being carried out at a temperature in the range from about-50° C. to -80° C.

The compounds of formula II where R⁴ is primary lower-alkyl and R⁵ isother than hydrogen, or R⁴ is secondary lower-alkyl and R⁵ is as definedfor formula I comprises reaction of a2-primary-lower-alkyl-R5-N,N-di-lower-alkylbenzamide (formula V, R⁴ isprimary-lower-alkyl) with one molar equivalent of a lower-alkyl lithiumor a lithium dilower-alkylamide, optionally in the presence of atetralower-alkylethylenediamine, in an inert organic solvent, forexample THF, and reaction of the resulting lithium salt with one molarequivalent of a lower-alkyl halide at a temperature in the range fromabout -50° C. to -80° C. The resulting 2-primary orsecondary-lower-alkyl-R⁵ -N,N-di-lower-alkyl-benzamide is thereafterconverted to the compounds of formula II, where R⁴ is primary orsecondary lower-alkyl, by the same sequence of reactions describedabove, i.e. by reaction of the 2-primary or secondary-lower-alkyl-R⁵-N,N-di-lower-alkyl-benzamide with one molar equivalent of a lower-alkyllithium; reaction of the resulting lithium salt either with sulfurdioxide followed by hydroxylamine-O-sulfonic acid in the presence ofbase or with a sulfuryl halide followed by ammonia; and cyclization ofthe product to the desired 4-primary or secondary-lower-alkyl-R⁵-saccharin of formula II. When the 2-lower-alkyl group in the2-lower-alkyl-R⁵ -N,N-di-lower-alkyl-benzamide starting material ismethyl, alkylation affords species where the 2-lower-alkyl group iseither straight or branched depending upon whether a straight orbranched chain lower-alkyl halide is used for the alkylation. On theother hand, when the 2-lower-alkyl group in the starting materialcontains more than one carbon atom, alkylation takes place on the carbonatom adjacent the benzene ring and affords products having asec.-lower-alkyl group at the 2-position.

A particularly useful method for the preparation of compounds II whereR⁴ is n-lower-alkyl and R⁵ is hydrogen involves the protection of thebenzylic protons of the starting material V with a trialkylsilyl group,thereby permitting lithiation at the 6-position and formation of thesulfonamide as described above. ##STR8## A 2-n-lower-alkylbenzamidewherein R⁸ is lower-alkyl is silylated by forming the benzylic anionusing an alkyllithium or, preferably, a lithium dialkylamide (i.e. LDA)in an inert solvent, preferably THF, and treating with a suitablechlorotrialkylsilane, preferably chlorotrimethylsilane. The saccharin issynthesized as before, and the silyl group is removed by treatment witha source of fluoride anion, preferably cesium fluoride in DMF ortetra-n-butylammonium fluoride in an inert solvent.

Access to certain of the required intermediates in some cases requiresbuilding up the two rings making up the saccharin nucleus. Thus toprepare saccharins where R⁴ is lower-alkoxy and R⁵ is 7-hydroxy, ortetrahydrosaccharins where R⁷ is lower-alkoxy, the following synthesismay be used: ##STR9## 3,3-Dithiobispropionic acid is converted to thebis acid chloride by reaction of the acid with thionyl chloride, and theacid chloride is then reacted with two molar equivalents of benzylamineto produce the bis N-benzylamide. The latter, on reaction with sulfurylchloride in an organic solvent, such as MDC, EDC or carbontetrachloride, affords 5-chloro-2-benzyl-2H-isothiazol-3-one, which isoxidized with one molar equivalent of a peracid, such as perbenzoic acidor 3-chloroperbenzoic acid, to5-chloro-2-benzyl-2H-isothiazol-3-one-1-oxide. The latter, on heatingunder pressure with a 2-lower-alkoxyfuran in an organic solvent, such asbenzene, toluene or xylene, affords a4-lower-alkoxy-7-hydroxy-2-benzyl-1,2-benzisothiazol-2H-3-one-1-oxide.The 7-hydroxy group can, if desired, then be reacted with a lower-alkylhalide or a lower-alkyl(O-lower-allkylene)_(p) -halide, where the halideis a chloride, bromide or iodide to give the corresponding4,7-di-lower-alkoxy or4-lower-alkoxy-7-[lower-alkyl-(O-lower-alkylene)_(p)-O]-2-benzyl-1,2-benzisothiazol-2H-3-one-1-oxide. Further oxidation ofthe product with one molar equivalent of a peracid as described abovefollowed by catalytic debenzylation by transfer hydrogenation affordsthe corresponding 4-lower-alkoxy-7-hydroxysaccharins.

When a tetrahydrosaccharin is desired, the following modification isused: ##STR10##

The 5-chloro-2-benzyl-2H-isothiazole-3-one-1-oxide may be oxidized witha suitable oxidizing agent, preferably hydrogen peroxide in acetic acid,to the 1,1-dioxide which is then reacted under typical Diels Alderconditions with the appropriate diene and reduced to provide the2-benzyl tetrahydrosaccharin which is hydrogenolyzed as before to thetetrahydrosaccharin.

Compounds of formula II wherein R⁴ is lower-alkyl or phenyl and R₅ ishydrogen may be synthesized by an alternate route from 2-cyclohexenone:##STR11##

2-Cyclohexenone is reacted with the appropriate cuprate, (R⁴)₂ CuZwherein Z is lithium or Mg(X')₂ and X' is a chloride, bromide or iodide,followed by methyl cyanoformate according to the method of Winkler etal. [Tet. Lett. 1987, 1051 and J. Org. Chem. 54, 4491 (1989)]. Theresulting β-ketoester is reacted with benzylmercaptan in the presence ofthe acidic clay Montmorillonite KSF to produce a mixture of regioisomersof the benzylthioenol ether. The mixture is aromatized by treatment withdichlorodicyanobenzoquinone (DDQ) and oxidized with chlorine gas inaqueous acid to provide the sulfonyl chloride ester, which may then beconverted to the intermediate II as shown earlier.

The 4,5,6,7-tetrahydrosaccharins which are the starting materials forthe compounds of formula VI wherein R⁷ is hydrogen are synthesized by aroute similar to the preceding one: ##STR12##

A 3-alkyl-2-cyclohexenone is reacted with the appropriate alkyl lithiumcuprate in an ethereal solvent, preferably diethyl ether, at -50° to+20°, preferably about 0°, and the resulting adduct is treated in situwith methyl cyanoformate and hexamethylphosphoramide. The6,6-dialkyl-2-oxocyclohexane carboxylate so produced is reacted withbenzyl mercaptan as described above and the mixture of 2-(benzylthio)cyclohexane carboxylates is oxidatively chlorinated as described aboveto provide a mixture of chlorosulfonyl esters that are treated withammonia as before to yield the desired4,4-dialkyl-4,5,6,7-tetrahydrosaccharins.

The heterocyclic carboxylic acids, HetCOOH; used to prepare the finalproducts of formula I are either commercially available or are membersof a known class and can be prepared by well-known, conventionalsynthetic methods.

Simple chemical transformations which are conventional and well known tothose skilled in the art of chemistry can be used for effecting changesin functional groups in the compounds of the invention. For example,catalytic reduction of nitro groups to produce the corresponding aminosubstituted compounds, acylation of amino-substituted species to preparethe corresponding amides, oxidation of sulfides or sulfoxides to preparethe corresponding, respective sulfoxides or sulfones, saponification ofesters to produce the corresponding carboxylic acids, catalyticdebenzylation of phenolic ethers or of benzylamines to produce thecorresponding phenols or debenzylated amines or reaction of phenols withan alkylating agent in the presence of base to produce ethers as desiredcan be carried out.

In standard biological test procedures, representative examples of thecompounds of the invention have been found to possess human leukocyteelastase (HLE) inhibitory activity, and are thus useful in the treatmentof degenerative diseases, such as emphysema, rheumatoid arthritis,pancreatitis, cystic fibrosis, chronic bronchitis, adult respiratorydistress syndrome, inflammatory bowel disease, psoriasis, bullouspemphigoid and alpha-1-antitrypsin deficiency.

The compounds of the invention having basic functions can be convertedto the acid-addition salt form by interaction of the base with an acid.In like manner, the free base can be regenerated from the acid-additionsalt form in conventional manner, that is by treating the salts withcold, weak aqueous bases, for example alkali metal carbonates and alkalimetal bicarbonates. The bases thus regenerated can be interacted withthe same or a different acid to give back the same or a differentacid-addition salt. Thus the bases and all of their acid-addition saltsare readily interconvertible.

Likewise the compounds of the invention having acid, i.e. carboxylicacid, functions can be converted to salt forms thereof by reaction ofthe acid with a base, such as alkali metal or ammonium hydroxides orwith organic bases such as alkyl, dialkyl or trialkylamines, and theacids can be regenerated from the salts by treatment of the salts withaqueous acids.

The pharmacological activity of the compounds of the invention can beenjoyed in useful form for pharmaceutical purposes by employing the freebases or free acids themselves or the salts formed from pharmaceuticallyacceptable acids and bases; that is, acids or bases whose anions orcations are innocuous to the animal organism in effective doses of thesalts so that beneficial properties inherent in the free bases and freeacids are not vitiated by side effects ascribable to the anions orcations.

In utilizing this pharmacological activity of the salt, it is preferred,of course, to use pharmaceutically acceptable salts. Although waterinsolubility, high toxicity or lack of crystalline character may makesome particular salt species unsuitable or less desirable for use assuch in a given pharmaceutical application, the water-insoluble or toxicsalts can be converted to the corresponding pharmaceutically acceptablebases by decomposition of the salts with aqueous base or aqueous acid asexplained above, or alternatively they can be converted to any desiredpharmaceutically acceptable salt by double decomposition reactionsinvolving the anion or cation, for example by ion-exchange procedures.

Moreover, apart from their usefulness in pharmaceutical applications,the salts are useful as characterizing or identifying derivatives of thefree bases or free acids or in isolation or purification procedures.Like all of the salts, such characterization or purification saltderivatives can, if desired, be used to regenerate the pharmaceuticallyacceptable free bases or free acids by reaction of the salts withaqueous base or aqueous acid, or alternatively they can be converted toa pharmaceutically acceptable salt by, for example, ion-exchangeprocedures.

The novel feature of the compounds then resides in the concept of the2-saccharinylmethyl heterocyclic carboxylates not in any particular acidor base moiety or acid anion or base cation associated with the saltforms of the compounds.

The compounds of the invention can be prepared for pharmaceutical use byincorporating them in unit dosage form as tablets or capsules for oraladministration either alone or in combination with suitable adjuvantssuch as calcium carbonate, starch, lactose, talc, magnesium stearate,gum acacia and the like. Still further, the compounds can be formulatedfor oral, parenteral or aerosol inhalation administration either inaqueous solutions of water soluble salts of the compounds or in aqueousalcohol, glycol or oil solutions or oil-water emulsions in the samemanner as conventional medicinal substances are prepared.

The percentages of active component in such compositions may be variedso that a suitable dosage is obtained. The dosage administered to aparticular patient is variable, depending upon the clinician's judgmentusing as criteria: the route of administration, the duration oftreatment, the size and physical condition of the patient, the potencyof the active component and the patient's response thereto. An effectivedosage amount of the active component can thus readily be determined bythe clinician after a consideration of all criteria and using his bestjudgment on the patient's behalf.

The molecular structures of the compounds of the invention were assignedon the basis of study of their infrared and NMR spectra. The structureswere confirmed by the correspondence between calculated and found valuesfor elementary analyses for the elements or by analysis of thehigh-resolution mass spectra.

The following examples will further illustrate the invention without,however, limiting it thereto. All melting points are in °C. and areuncorrected.

PREPARATION OF STARTING MATERIALS Preparation 1

Powdered potassium hydroxide (7.4 g, 0.132 mol) was admixed withdimethyl sulfoxide (DMSO) (100 ml), and the mixture was stirred for 5minutes. 6-Methylanthranilic acid (10.0 g, 0.066 mol) was then added tothe mixture and iodomethane (4.52 ml, 0.073 mol) added dropwise. Thereaction mixture was stirred for 30 minutes at room temperature, thendiluted with 250 ml of ether, washed with water (3×100 ml), dried overmagnesium sulfate and concentrated. The crude product was filteredthrough a pad of flash grade (32-63) silica gel and eluted with 1:9ether:hexane to afford 4.23 g (39%) of methyl 6-methylanthranilate as anoil.

The methyl 6-methylanthranilate so prepared (4.23 g, 0.026 mol) wasdissolved in 25 ml of acetic acid and the solution cooled to 0° C.Concentrated hydrochloric acid (45 ml) was added to produce a tanslurry. A solution of 1.89 g (0.027 mol) of sodium nitrite in 8 ml waterwas added dropwise with stirring, the resulting orange solution wasstirred at 0° C. for 1 hour and then added in 6 portions to a mixture of2.18 g (0.013 mol) of cuptic chloride dihydrate and sulfur dioxide (6.3g) in 33 ml of acetic acid and 6 ml of water at 0° C. The dark greensolution was stirred at room temperature overnight, poured into 300 mlof ice-water, and the solid which separated was collected and dried bysuction to provide 1.11 g of methyl 2-chlorosulfonyl-6-methylbenzoatewhich was immediately added to 100 ml of ice cold ammonium hydroxide andstirred at room temperature overnight. The solution was acidified to pH1 with concentrated hydrochloric acid, and the resulting precipitate wascollected and air-dried to provide 729 mg (12%) of 4-methylsaccharin, mp224°-226° C.

A mixture of 1.0 g (0.005 mol) of 4-methylsaccharin, 0.33 g (0.001 mol)of TBAB and 1.2 g (0.0075 mol) of chloromethyl phenyl sulfide in 25 mlof toluene was heated under reflux for about sixteen hours and thencooled, diluted with ethyl acetate and the solution washed with aqueousbicarbonate and water. The organic layer was dried and taken to drynessto give 0.74 g of 2-phenylthiomethyl-4-methylsaccharin.

The latter (0.74 g, 0.002 mol) was dissolved in 25 ml of MDC and thesolution treated dropwise over a period of about two hours with stirringwith a solution of 0.47 g (0.003 mol) of sulfuryl chloride in MDC andthe reaction mixture taken to dryness. The yellow residual solid wastriturated with hexane and filtered and dried to give 0.46 g of2-chloro-methyl-4-methylsaccharin as a pale yellow solid.

Preparation 2

Using the procedure described above in Preparation 1, 5.0 g (0.029 mol)of 6-chloroanthranilic acid and 2.75 ml (0.044 mol) of iodomethane werereacted in the presence of 4.08 g (0.073 mol) of powdered potassiumhydroxide to give 4.22 g (78%) of methyl 6-chloroanthranilate as an oil.

4-Chlorosaccharin was prepared by the same method as used for thepreparation of 4-methylsaccharin using 4.22 g (0.023 mol) of methyl6-chloroanthranilate in 22 ml of acetic acid and 40 ml of concentratedhydrochloric acid and 1.68 g (0.024 mol) of sodium nitrite in 7 ml ofwater to prepare the diazonium salt which was added to 1.93 g (0.011mol) of cupric chloride dihydrate and 6.5 g of sulfur dioxide in 30 mlof acetic acid and 5 ml of water. The resulting methyl2-chlorosulfonyl-6-chlorobenzoate was treated with 150 ml of ammoniumhydroxide as described above to afford 3.07 g (62%) of 4-chlorosaccharinas a pale yellow solid, mp 245°-246° C.

2-Hydroxymethyl-4-chlorosaccharin was prepared by heating a solution of1.00 g (0.0046 mol) of 4-chlorosaccharin and 3.22 ml of aqueous 37%formalin in ethanol. All attempts to crystallize the viscous oilyproduct resulted in decomposition to the starting material, and theproduct was thus used in the next step without characterization.

The crude 2-hydroxymethyl-4-chlorosaccharin so prepared (609 mg, 0.0025mol) was admixed with 5 ml of diethylether, and 3 ml of thionyl chloridewas added. The resulting mixture was heated to effect complete solution,stirred at room temperature overnight, diluted with 20 ml of ether andfiltered through a pad of celite topped with sand and eluted with ether.Removal of the solvent afforded 430 mg of crude chloromethyl derivative.A portion (225 mg) was removed for further reactions. The remainder (205mg) was flash chromatographed on silica gel and eluted with 40%ether/pentane to provide 137 mg of 2-chloromethyl-4-chlorosaccharin, mp135°-136° C.

Preparation 3A

To a suspension of 6.0 g (0.03 mol) of cuprous iodide in 100 ml of THFwas added 25 ml of dimethyl sulfide, and the resulting yellow solutionwas cooled to -78° C. and treated dropwise with a solution of 23 ml(0.06 mol) of a 3.0M solution of phenyl magnesium bromide in diethylether. The resulting pale yellow-orange solution was stirred at -78° C.under nitrogen for one hour and then treated with 3.02 g (0.03mol) of2-cyclohexenone in 10 ml of THF. The resulting mixture was allowed towarm to 0° C. over a two hour period, recooled to -78° C. treated with15 ml of hexamethylphosphoramide, stirred for thirty minutes, treatedwith 8.0 g (0.09 mol) of methyl cyanoformate and allowed to warm toambient temperature overnight. The reaction mixture was poured into 100ml of 2N hydrochloric acid, and the organic phase was separated and theaqueous phase back-extracted with MDC. The combined organic extractswere taken to dryness in vacuo and the residue triturated with saturatedammonium chloride, then with water, then with brine and taken to drynessonce again to give 3.2 g of methyl 2-phenylcyclohexan-6-one carboxylateas an oil.

The latter (3.0 g, 0.013 mol), 4.8 g (0.039 mol) of benzyl mercaptan and1.0 g of Amberlyst®-15 resin (Rohm and Haas) in chloroform was heatedunder reflux for twenty hours, the mixture treated with an additional1.5 g of the resin and heated for an additional four hours. The mixturewas then cooled to ambient temperature, filtered, the filtrate taken todryness in vacuo, the residue triturated with hexane and the solidcollected by filtration to give 0.85 g (19%) of a mixture ofmethyl-2-benzylthio-6-phenylcyclohe-2-ene carboxylate and methyl2-benzylthio-6-phenylcyclohex-1-ene carboxylate, 0.6 g (0.0018 mol) ofwhich was heated with 2.0 g of 2,3-dichloro-5,6-dicyanobenzoquinone in25 ml of toluene with stirring under nitrogen for twenty-four hours. Themixture was filtered through a pad of silica gel, eluting with 2:1MDC:hexane, and the eluate was taken to dryness to give 0.3 g (67%) ofmethyl 2-benzylthio-6-phenylbenzoate.

The latter (0.52 g, 0.0016 mol) dissolved in 10 ml of MDC was dilutedwith 20 ml of acetic acid and 5 ml of water, the mixture cooled to -10°C. and chlorine gas was bubbled through the mixture until the exothermicreaction subsided. The mixture was then stirred for ten minutes andtaken to dryness in vacuo to give 0.41 g (85%) of methyl2-chlorosulfonyl-6-phenylbenzoate which was dissolved in 10 ml of THFand added to 25 ml of a solution of concentrated ammonium hydroxidewhile cooling in an ice/acetone bath. The reaction mixture was extractedwith MDC, the organic phase discarded, and the aqueous layer acidifiedto pH 1 with concentrated hydrochloric acid and extracted with MDC. Theorganic extracts, on washing with brine, drying and evaporation todryness, afforded 0.33 g (97%) of 4-phenylsaccharin.

Following a procedure similar to that described in Preparation 1, thelatter (0.33 g, 0.0012 mol) was reacted with 0.3 g (0.0019 mol) ofchloromethyl phenyl sulfide in 15 ml of toluene in the presence of 0.08g (0.0025 mol) of TBAB and the product,2-phenylthiomethyl-4-phenylsaccharin (0.48 g, 100%), treated withsulfuryl chloride in MDC to give 0.36 g (95%) of2-chloromethyl-4-phenylsaccharin.

Preparation 3B

To a suspension of anhydrous CuCN (2.16 g, 0.025 mol) in anhydrous ether(100 mL) at -78° C. was added tert butyllithium (29.0 mL of 1.7Msolution in pentane, 0.05 mol). After being stirred at -78° C. for 1 hrand at -45° C. for 30 minutes, the reaction mixture was recooled to -78°C. A solution of cyclohexenone (2.4 g, 0.025 mol) in ether (25 mL) wasadded and stirring continued for 15 minutes at -78° C. and at -45° C.for 30 minutes The resulting mixture was recooled to -78° C. and HMPA(10 mL) in ether (25 mL) was added. After 5 min, methyl cyanoformate(2.55 g, 0.03 mol) in ether (25 mL) was added and the reaction warmed to0° C. over a 2 hr period. The resulting mixture was quenched with 2N HCl(100 mL), the layers were separated, and the organic phase was washedwith saturated NH₄ Cl solution (3×50 mL), water (2×50 mL), brine (1×50mL) and dried (Na₂ SO₄) . Removal of the solvent in vacuo andpurification by Kugelrohr distillation (bath temperature 100°-115° C. at0.6 mm) afforded 4.7 g (88%) of methyl2-(1,1-dimethylethyl)cyclohexan-6-one-carboxylate.

The cyclohexanone (4.6 g, 0.022 mol) was mixed with benzylmercaptan(2.95 g, 0.024 mol) and the acidic clay montmorillonite, KSF (7.5 g) inanhydrous toluene (7.5 mL). The mixture was refluxed under nitrogen withazeotropic removal of water for 6 hr, cooled to room temperature and letstand overnight. The solids were filtered off and washed with ether. Thecombined filtrate was washed with 10% Na₂ CO₃, water, brine and dried.Removal of the solvent in vacuo and purification of the residue by flashchromatography on silica gel (10% ether in hexanes) gave 4.4 g (66% of amixture of methyl 2-benzylthio-6-(1,1-dimethylethyl]cyclohex-2-enecarboxylate and 2-benzylthio-6-(1,1-dimethylethyl]cyclohex-1-enecarboxylate, which was stirred with DDQ (17.5 g, 0.077 mol) in toluene(50 mL) for 16 hr. The red reaction mixture was filtered through a 15 cmpad of silica gel, eluting with 6:3:1 hexanes:MDC:ether (1000 mL). Theeluents were washed with 10% NaOH solution, water, brine and dried.Removal of the solvent in vacuo and purification by chromatography onsilica gel (5% ether in hexanes) gave 1.6 g (40%) of methyl2-benzylthio-6-(1,1-dimethyl)benzoate.

The benzylthiobenzoate (1.3g, 0.004 mol) dissolved in MDC (5 mL) wasdiluted with acetic acid (25 mL) and water (2 mL), the mixture cooled to-10° C. and chlorine gas was bubbled until the exothermic reactionsubsided. The mixture was then stirred for 10 minutes and taken todryness in vacuo. Purification of the residue by flash chromatography onsilica gel (1:1 hexanes:MDC) gave 0.8 g (67%) of methyl2-chlorosulfonyl-6-(1,1-dimethylethyl)benzoate, which was dissolved inTHF (5 mL) and added to a solution of concentrated ammonium hydroxide(25 mL) while cooling in an ice/acetone bath. After stirring at roomtemperature for 16 hr, the reaction mixture was concentrated in vacuoand acidified to pH 1 with 2N HCl. The separated solids were collectedby filtration and cystallized from ether to give 0.64 g (95%) of4-(1,1-dimethylethyl]saccharin, mp 185°-187° C.

The 4-(1,1-dimethylethyl) saccharin (0.025 g 1.0 mmol) was mixed withchloromethyl phenyl sulfide (0.25 g, 1.5 mmol) and tetrabutyl ammoniumbromide (0.2 g, 0.6 mmol) in toluene (25 mL) and refluxed under nitrogenfor 16 hr. The resulting mixture was cooled to room temperature,evaporated to dryness and purified by chromatography on silica gel (80%)MDC in hexanes) to give 0.35 g (98%) of2-phenylthiomethyl-4-(1,1-dimethylethyl]saccharin, which was treatedwith sulfuryl chloride (0.25 g, 1.8 mmol) in MDC to give 0.21g (75%) of2-chloromethyl-4-(1,1-dimethylethyl]saccharin.

Preparation 4

A mixture of 3.22 g (0.012 mol) of 4-bromosaccharin [Japanese Pat.Publcn. 58/79,034, published May 12, 1983; C.A. 100, 7773w (1984)], 1.63g (0.015 mol) of potassium t-butoxide, 0.39 g (0.0012 mol) of TBAB and3.0 ml (0.022 mol) of chloromethyl phenyl sulfide in 100 ml of toluenewas heated under reflux under a nitrogen atmosphere for eight hours andthen stirred at ambient temperature for about sixteen hours. Thereaction mixture was then diluted with ethyl acetate, and the organiclayer was washed with dilute potassium carbonate, water and brine, driedover magnesium sulfate and taken to dryness in vacuo. The residual solidwas recrystallized from toluene-hexane to give 3.86 g (84%) of4-bromo-2-phenyl-thiomethylsaccharin, mp 174.5°-178° C.

To a solution of the latter (3.27 g, 0.0085 mol) in 85 ml of MDC wasadded, dropwise with stirring, 1.02 ml (0.0127 mol) of sulfurylchloride. The mixture was stirred at ambient temperature for an hour anda half, concentrated in vacuo and the residue triturated with hexane andfiltered to give 2.61 g of crude product which was recrystallized fromtoluene-hexane to give 2.24 g (85%) 2-chloromethyl-4-bromosaccharin, mp157°-159° C.

Preparation 5

To a solution of 8.0 ml (0.053 mol) of tetramethylethylenediamine(TMEDA) in 350 ml of THF at -70° C. was added 42 ml (0.055 mol) of a1.3M solution of s-butyl lithium in cyclohexane and the mixture wasstirred for fifteen minutes. To the solution was added dropwise withstirring a solution of 10.36 g (0.050 mol) of2-methoxy-N,N-diethylbenzamide in 150 ml of THF while maintaining thetemperature at -60° C. or below. After stirring for 20 minutes sulfurdioxide was bubbled into the reaction mixture, keeping the reactiontemperature below -50° C. until the reaction mixture was acid to wetlitmus paper. The mixture was stirred at ambient temperature for twohours, diluted with 450 ml of hexane, and the solid material which hadseparated was collected, dissolved in 200 ml of water and the mixturetreated with 65 g of sodium acetate and 21.5 g (0.19 mol) ofhydroxylamine-O-sulfonic acid in portions with stirring. The white solidwhich separated was collected and dried to give 7.04 g (49%) of2-aminosulfonyl-6-methoxy-N,N-diethylbenzamide, mp 190°-194.5° C.

A mixture of the product (4.3 g, 0.015 mol) in 75 ml of dioxane and 25ml of concentrated hydrochloric acid was heated on a steam bath for 70hours, then cooled, concentrated in vacuo, diluted with water and iceand rendered strongly basic with concentrated sodium hydroxide. Themixture was washed with MDC, and the aqueous layer was acidified withdilute hydrochloric acid and extracted with MDC. The extracts were driedover magnesium sulfate and taken to dryness to give 1.29 g (40%) of4-methoxysaccharin. In an alternative, and preferred, procedure,cyclization of 2-aminosulfonyl-6-methoxy-N,N-diethylbenzamide to4-methoxysaccharin in 65% yield was carried out in refluxing glacialacetic acid for six and a half hours.

Following a procedure similar to that described in Preparation 4 above,1.14 g (0.0053 mol) of the latter was reacted with 1.31 ml (0.0097 mol)of chloromethyl phenylsulfide in toluene in the presence of 0.72 g(0.0064 mol) of potassium t-butoxide and 174 mg (0.00054 mol) oftetrabutylammonium bromide to give 1.23 g (69%) of4-methoxyl-2-phenylthiomethylsaccharin, mp 152.5°-154.5° C. (from ethylacetate-hexane), 1.02 g (0.003 mol) of which was treated with 0.36 ml(0.0045 mol) of sulfuryl chloride in MDC to give 282 mg (36%) of2-chloromethyl-4-methoxy-saccharin, mp 169°-174° C.

Preparation 6A

To a solution of 4.74 ml (0.031 mol) of tetramethylethylenediamine in300 ml of THF (passed through alumina prior to use) was added 5.8 g(0.03 mol) of 2-ethyl-N,N-diethylbenzamide. The solution was cooled to-78° C. and treated with 34.9 ml (0.031 mol) of a 0.9M solution ofs-butyl lithium in cyclohexane. When addition was complete, the mixturewas stirred for twenty minutes and then treated with a solution of 3.2ml (0.04 mol) of ethyl iodide while maintaining the temperature at -78°C. The temperature was then allowed to rise to ambient temperature andthe mixture stirred for about sixteen hours and then poured into water.The resulting oil was separated and chromatographed on silica gel,eluting with 10% ethyl acetate/hexane to give 2.86 g (43%) of2-sec.-butyl-N,N-diethylbenzamide as a yellow oil.

Following a procedure similar to that described in Preparation 5 above,the latter (10.45 g, 0.045 mol), dissolved in 70 ml of THF, was added toa solution of 39.2 ml (0.047 mol) of a 1.2M solution of s-butyl lithiumin cyclohexane and 7.1 ml (0.047 mol) of tetramethylethylenediamine in250 ml of THF while maintaining the temperature at -78° C. When additionwas complete the mixture was stirred for an additional one half hour at-78° C. and then treated with sulfur dioxide at -70° C. and then allowedto warm to room temperature. The mixture was taken to dryness in vacuo,and the residue was dissolved in water and added with stirring to a coldsolution of 15.2 g (0.134 mol) of hydroxylamine-O-sulfonic acid and 15.4ml (0.134 mol) of 35% sodium hydroxide to give 10.1 g (72%) of2-aminosulfonyl-6-sec.-butyl-N,N-diethylbenzamide.

The latter (6.83 g, 0.22 mol) was dissolved in 100 ml of glacial aceticacid and the solution heated under reflux for thirteen hours and thentaken to dryness. The residue was triturated with diethyl ether andcollected by filtration to give 5.7 g (83%) of the diethylammonium saltof 2-sec.-butylsaccharin.

The latter (3.0 g, 0.0096 mol), on reaction with 1.13 ml (0.012 mol) ofchloromethyl phenyl sulfide in toluene, afforded 3.47 g (100%) of2-phenylthiomethyl-4-sec.-butyl, saccharin.

Reaction of the latter (3.2 g, 0.0097 mol) with 2.3 ml (0.029 mol) ofsulfuryl chloride in 20 ml of MDC afforded 2.4 g (87%) of2-chloromethyl-4-sec.-butylsaccharin.

Preparation 6B

By a procedure analogous to that described for Preparation 6A, 9.2 g(32.9 mmol) of 3,4-dimethoxy-2-propyl-N,N-diethylbenzamide was reactedwith sulfur dioxide and 5.6 g (49.4 mmol) of hydroxylamine-O-sulfonicacid to provide 7.4 g (63%) of2-aminosulfonyl-4,5-dimethoxy-6-propyl-N,N-dimethylbenzamide which wascyclized in quantitative yield in acetic acid and phenylthiomethylatedwith 1.42 mL (15 mmol) of chloromethyl phenyl sulfide to provide 4.07 gof 5,6-dimethoxy-2-phenylthiomethyl-4-propylsaccharin. Reaction of 3.59g (8.8 mmol) of the phenylthioether with 2.12 mL (26.4 mmol) sulfurylchloride provided 2.84 g (97%) of2-chloromethyl-5,6-dimethoxy-4-propylsaccharin.

The 3,4-dimethoxy-2-propyl-N,N-diethylbenzamide was obtained by thefollowing procedure:

To a solution of 0.216 moles of n-butyllithium in 250 mL of ether atambient temperature was added dropwise 138.2 g (0.216 mol) of veratrolin 100 mL of ether and 32.6 mL (0.216 mol) of TMEDA. The reaction wasstirred at ambient temperature 14 hours and 21.9 mL (0.225 mol) ofn-propyl iodide was added with cooling. The reaction was stirred 1 hourat RT and worked up with aqueous IN HCl to give 14 g (36%) of2,3-dimethoxybenzenepropane which was brominated with 14.52 g (81.6mmol) of N-bromosuccinimide on 36 g of Kieselgel in 400 mL of CCl₄according to the method of Hisatoshi et al. [Bull. Chem. Soc. Jap. 32,591-593 (1989)] to give 19.6 g (98%) of6-bromo-2,3-dimethoxybenzenepropane.

The bromobenzene (14.2 g, 54.8 mmol) was dissolved in 200 mL ether,cooled to -78° and 25.2 mL (63 mmol) of 2,5 N n-butyllithium in hexanewas added The reaction was warmed to 0°, held for an hour, and cooled to-70° and 9 mL (71.2 mmol) of diethyl carbamyl chloride was added. Thereaction was allowed to come to RT and was quenched with saturatedammonium chloride. After extraction and drying, the product wascrystallized from hexane to provide 9.5 g (62%) of3,4-dimethoxy-2-propyl-N,N-diethylbenzamide, mp 65°-67°.

Preparation 6C

By a process analogous to that of preparation 6B, 10.75 g (30 mmol) of6-aminosulfonyl-3,4-dimethoxy-2-isopropyl-N,N-diethylbenzamide wascyclized to provide 6.43 g of 5,6-dimethoxy-4-isopropyl saccharin (top186-188 from ether-hexane), 5 g (17.5 mmol) of which wasphenylthiomethylated with 2.48 mL (26.3 mmol) ofphenylthiomethylchloride according to the procedure of Preparation 5,and chlorinated with 3 equivalents of sulfuryl chloride to provide an85% yield of 2-chloromethyl-5,6-dimethoxy-4-isopropylsaccharin mp117°-119° from ethyl acetate-hexane.

The requisite benzamide was obtained from2,3-dimethoxy-α-methylbenzeneethane by bromination followed bycarbamylation as in Preparation 6B, to provide the intermediate3,4-dimethoxy-2-isopropyl-N,N-diethylbenzamide. A solution of 66 mL of0.96M sec-butyllithium was added to 16.1 g (57.6 mmol) of the benzamidein 400 mL of THF at -78° under nitrogen. After stirring 2 hours theorange anion was cannulated into excess sulfur dioxide at -60°. Thereaction was allowed to come to room temperature and stirred for 18 hrsto remove SO₂. Ten milliliters of sulfuryl chloride was added at 0° andthe reaction was stripped. The sulfonyl chloride was extracted intoEtOAc-ether, washed with water, dried and stripped. The residue wasdissolved in 80 mL of THF and 17 mL of conc. NH₄ OH was added at 0°. Thereaction was stirred briefly at RT, stripped, and triturated in 2:1ether-hexane to provide 12.89 g (62%) of6-aminosulfonyl-3,4-dimethoxy-2-isopropyl-N,N-diethylbenzamide, mp138°-140°.

Preparation 7

To a solution of 9.3 ml (0.058 mol) of tetramethylethylenediamine in 340ml of THF at -78° C. was added 52 ml of a 1.1M solution (0.057 mol) ofs-butyl lithium in cyclohexane. The solution was then treated with asolution of 11.37 g (0.052 mol) of 2-propyl-N,N-diethylbenzamide in 75ml of THF at -78° C. and the solution stirred for fifteen minutes andthen treated with a solution of 8.3 ml (0.104 mol) of ethyl iodide inTHF. The solution was stirred for an hour and a half at -78° C. and thenquenched by the addition of saturated ammonium chloride added dropwiseat -78° C. The mixture was then allowed to warm to ambient temperature,diluted with diethyl ether, washed first with dilute hydrochloric acid,then with water, then with saturated sodium bicarbonate, then withbrine, dried and taken to dryness to give 12.91 g of crude product whichwas chromatographed on silica gel, eluting with 10% ethyl acetate/hexaneto give 3.23 g (25%) of 2-(3-pentyl)-N,N-diethylbenzamide as a yellowoil.

Following a procedure similar to that described in Preparation 5 above,the latter (3.05 g, 0.0115 mol) in THF was reacted with 10.5 ml (0.126mol) of a 1.2M solution of s-butyl lithium in cyclohexane in thepresence of 2.1 ml (0.014 mol) of tetramethylethylenediamine. Theresulting lithium salt was then reacted first with sulfur dioxide andthen with sodium hydroxylamine-O-sulfonate to give 1.97 g (52%) of2-aminosulfonyl-6-(3-pentyl]-N,N-diethylbenzamide as pale yellowcrystals, mp 118°-120° C. (soft 102°), 1.84 g (0.0056 mol) of which wascyclized in 22 ml of refluxing glacial acetic acid to give 1.28 g (70%)of the diethylammonium salt of 4-(3-pentyl)saccharin, mp 107.5°-109.5°C.

The latter (0. 0037 mol), on reaction with 0.74 ml (0.0055 mol) ofchloromethyl phenyl sulfide in the presence of 116 mg (0.0004 mol) ofTBAB in 45 ml of toluene, afforded 1.93 g of2-phenylthiomethyl-4-(3-pentyl]saccharin as a pale yellow oil, 1.93 g(0.0037 mol) of which, on reaction with 0.59 ml (0.0073 mol) of sulfurylchloride in 37 ml of MDC, afforded 1.2 g of2-chloromethyl-4-(3-pentyl]saccharin as a pale yellow oil.

Preparation 8

A solution of 50.0 g (0.27 mol) of 2,4-dimethoxybenzoic acid in 60 ml(98.0 g, 0.82 mol) of thionyl chloride was heated under reflux for threehours, then cooled, and the excess thionyl chloride distilled off. Theresulting 2,4-dimethoxybenzoyl chloride was dissolved in 150 ml of MDCand the solution treated with a solution of 68 ml (48 g, 0.66 mol) ofdiethylamine in 500 ml of MDC, cooled to 0° C. When addition wascomplete the mixture was stirred for fifteen hours at ambienttemperature, then washed with saturated sodium bicarbonate, water andbrine and taken to dryness and the residue distilled in vacuo to give44.78 g (69%) of 2,4-dimethoxy-N,N-diethylbenzamide, b.p. 155°-163°C./0.4 mm.

Following a procedure similar to that described in Preparation 5 above,10.0 g (0.042 mol) of the product in 250 ml of THF was reacted with40.57 ml of a 1.1M solution (0.044 mol) of s-butyl lithium incyclohexane and 6.35 ml (0.042 mol) of tetramethylethylenediamine inTHF. The resulting lithium salt was then reacted first with about 40 mlof sulfur dioxide and then with an aqueous solution (0.13 mol) of sodiumhydroxylamine-O-sulfonate to give 8.26 g of2-aminosulfonyl-4,6-dimethoxy-N,N-diethylbenzamide, 7.0 g of which(0.022 mol) was cyclized in 80 ml of refluxing glacial acetic acid togive 6.6 g (94%) of the diethylammonium salt of 4,6-dimethoxy-saccharinwhich was used as such in the next step without further purification.

The latter (6.0 g, 0.019 mol), on reaction with 3.82 ml (0.028 mol) ofchloromethyl phenyl sulfide in the presence of 0.611 g (0.0019 mol) ofTBAB in 200 ml of toluene, afforded 6.2 g (89%) of2-phenylthiomethyl-4,6-dimethoxysaccharin, 5.82 g of which (0.016 mol),on reaction with 3.23 g (0.0019 mol) of sulfuryl chloride in 100 ml ofMDC, afforded 4.63 g (100%) of 2-chloromethyl-4,6-dimethoxysaccharin,m.p. 185°-187° C.

Preparation 9A-9G

Following a procedure similar to that described above in Preparation 5,substituting for the 2-methoxy-N,N-diethylbenzamide used therein anappropriate 2-R⁴ -R⁵ -substituted-N,N-diethylbenzamide, the following2-halomethyl-4-R⁴ -R⁵ -saccharins listed in TABLE A were prepared viathe corresponding 2-phenylthiomethylsaccharins- Wherever available, themelting point, recrystallization solvent and yield are given for each ofthe 2-unsubstituted saccharins, the 2-phenylthiomethylsaccharins and the2-chloromethylsaccharins in columns headed "mp/Solv." and "Yield". Inall instances, the intermediate 2-phenylthiomethylsaccharins were useddirectly in the subsequent step without further characterization orpurification.

                                      TABLE A                                     __________________________________________________________________________                Sacc        2-C.sub.6 H.sub.5 SCH.sub.2 -Sacc                                                        2-ClCH.sub.2 -Sacc                         Prep                                                                              R.sup.4 /R.sup.5                                                                      mp/Solv                                                                              Yield                                                                              mp/Solv                                                                             Yield                                                                              mp/Solv   Yield                            __________________________________________________________________________    9A  H       260-262                                                                              93   --    100  158.0-160.0                                                                             51                                   7-Cl                           i-PrOH                                     9B  CH(CH.sub.3).sub.2                                                                    177.0-178.0                                                                          88   --    100  93.0-96.0 100                                  H       MeOH                   i-PrOH-Cyc hex                             9C  CH.sub.3 O                                                                            (a)    64   --    100  190.0-192.0                                                                             76                                   5-CH.sub.3 O                                                              9D  COOCH.sub.3                                                                           (b)    76   --    65   186.0-187.0                                    H       EtOAc-hex                                                         9E  C.sub.2 H.sub.5 O                                                                     (a)    96   --    95   139.0-140.0                                                                             97                                   H                                                                         9F  (CH.sub.3).sub.2 CHO                                                                         87   --    75   142.5-143.5                                                                             94                                   H                                                                         9G  C.sub.2 H.sub.5                                                                       i-PrOH 67   --    52   --        99                                   5,7-(CH.sub.3 O).sub.2                                                    __________________________________________________________________________     (a) Isolated and used in the next step as the diethylammonium salt.           (b) The 2unsubstituted-saccharin was prepared by cyclization of dimethyl      3aminosulfonylphthalate in methanol in the presence of a molar equivalent     of sodium methoxide. The phthalate ester was prepared by diazotization of     dimethyl 3aminophthalate, decomposition of the diazonium salt with sulfur     dioxide in the presence of cupric chloride and reaction of the resulting      dimethyl 2chlorosulfonylphthalate with ammonia. (84% yield overall).     

Preparation 10

Following a procedure similar to that described in Preparation 2,reaction of 18.3 g (0.1 mol) of saccharin with 70 ml of 37% formalin inethanol afforded 3.58 g (70%) of 2-hydroxymethylsaccharin. The latter(25 g, 0.117 mol) was reacted with 63.3 g (0.234 mol) of phosphorustribromide in diethyl ether to give 29.8 g (92%) of2-bromomethylsaccharin, mp 155°-157° C.

Preparation 11

To a solution of 4 g (0.0175 mol) of 6-nitrosaccharin in 240 ml ofethanol was added 4.4 g (0.0175 mol) of thallium ethoxide, and themixture was allowed to stand at room temperature for one hour, cooledfor about 16 hours and the precipitated solid collected and dried togive 7.6 g (100%) of the thallium salt of 6-nitrosaccharin. The productwas suspended in 50 ml of DMF and the mixture treated with 3.07 g(0.0194 mol) of chloromethyl phenyl sulfide, the mixture warmed at about63° C. for five hours, allowed to stand at ambient temperature for about16 hours, and then poured into ice water. The crude product, obtained byfiltration, was stirred in MDC and filtered to remove thallium salts.The filtrate was freed of solvent, and the resultant pale yellow solidwas sonicated with warm ethanol and once again collected and dried togive 4.6 g (75%) of 6-nitro-2-phenylthiomethylsaccharin, mp 161°-163° C.The latter, on reaction with sulfuryl chloride in MDC using theprocedure described above in Preparation 4, afforded 3.7 g of2-chloromethyl-6-nitrosaccharin.

Preparation 12

A solution of 4 9.8 g (0.199 mol) of2-hydroxy-5-(1,1,3,3-tetramethylbutyl)benzoic acid in 200 ml of methanolwas heated to 50° C. and then treated dropwise with about 80 g ofsulfuric acid at a rate to maintain the reaction under reflux. Thereaction mixture was heated under reflux for an additional 11 hours,then cooled and partitioned between water and ethyl acetate. The organiclayer was washed with saturated sodium bicarbonate, then with brine,dried over sodium sulfate and taken to dryness to give 48.6 g (92%) ofmethyl 2-hydroxy-5-(1,1,3,3-tetramethylbutyl]benzoate.

The latter dissolved in 250 ml of DMF was treated first with 40.4 g(0.36 mol) of 1,4-diazabicyclo[2.2.2]octane followed by 33.4 g (0.27mol) of N,N-dimethylchlorothiocarbamate and 100 ml of DMF. The reactionmixture was heated at 45° C. for about eight hours, cooled, poured intoice/water and concentrated hydrochloric acid and then extracted withethyl acetate. The combined organic extracts were washed with dilutehydrochloric acid, then with sodium bicarbonate and then with brine,dried and taken to dryness to give 48.2 g (76%) of methyl2-(N,N-dimethylthiocarbamyloxy)-5-(1,1,3,3-tetramethylbutyl)benzoatewhich was heated at 220° C. for 15 hours, then cooled, dissolved intoluene and chromatographed on silica, eluting with 1:9 ethylacetate:toluene, to give 3.6 g (14%) of methyl2-(N,N-dimethylcarbamylthio)-5-(1,1,3,3-tetramethylbutyl)benzoate.

A solution of the latter (0.025 mol) in 40 ml of MDC was treated, withstirring, with 80 ml of glacial acetic acid, followed by 16 ml of water.The reaction mixture was cooled to 0° C. and chlorine was bubbledthrough the reaction mixture for about five minutes while maintainingthe temperature between 5° and 24° C. The reaction was stirred for anadditional 30 minutes, concentrated/a vacuo, and the remaining solutionpoured into ice water. Extraction of the mixture with ethyl acetate andisolation of the product from the combined organic extracts afforded 6.8g (78%) of methyl 2-chlorosulfonyl-5-(1,1,3,3-tetramethylbutyl)benzoate.

The product (9.0 g, 0.026 mol) was dissolved in THF and added to 100 mlof concentrated ammonium hydroxide with cooling in an ice bath. Theresulting solution was stirred for about 16 hours, then concentrated invacuo and the concentrated solution acidified to pH 3 with concentratedhydrochloric acid. The mixture was stirred for several hours, and theseparated solid collected, washed with water and dried to give 9.0 g of5-(1,1,3,3-tetramethylbutyl]saccharin, mp 213°-215° C.

Following a procedure similar to that described in Preparation 11, 9.0 g(0.30 mol) of the product was reacted with thallium ethoxide in ethanoland the resulting thallium salt reacted with 3.33 g (0.021 mol) ofchloromethyl phenylsulfide in DMF to give 5.76 g (66%) of2-phenylthiomethyl-5-(1,1,3,3-tetramethylbutyl]saccharin, 3.3 g (0.007mol) of which was treated with 0.944 g of sulfuryl chloride in MDC togive 1 g (41%) of 2-chloromethyl-5-(1,1,3,3-tetramethyl-butyl)saccharin.

Preparation 13

Following a procedure similar to that described in Preparation 12 above,15.5 g (0.086 mol) of ethyl 2-hydroxy-6-methylbenzoate was reacted with15.9 g (0.129 mol) of N,N-dimethylchlorothiocarbamate in the presence of19.3 g (0.172 mol) of 1,4-diazabicyclo[2.2.21octane in DMF to give 22.1g (96%) of ethyl 2-N,N-dimethylthiocarbamyloxy)-6-methylbenzoate whichwas heated at 220° C. for about 10 hours. The product was purified bychromatography on silica gel in MDC to give ethyl2-(N,N-dimethylcarbamylthio)-6-methylbenzoate as a red-brown oil.

A solution of the latter (22.6 g, 0.0844 mol) in 170 ml of MDC wastreated with 340 ml of glacial acetic acid and 68 ml of water whilecooling in an ice/acetone bath, and chlorine was bubbled through thereaction mixture for 10-15 minutes. The reaction vessel was evacuated toremove excess chlorine and MDC and the mixture poured into water andpartitioned between MDC and water. The organic layer, on drying andevaporation to dryness, afforded 19 g of ethyl2-Chlorosulfonyl-6-methylbenzoate, 5 g (0.019 mol) of which was reactedwith concentrated ammonium hydroxide in THF to give 6.1 g (67%) of4-methylsaccharin.

Following a procedure similar to that described in Preparation 11 above,the product (10.1 g, 0.0512 mol) was converted to the thallium salt byreaction with 12.8 g (0.0512 mol) of thallium ethoxide in ethanol andthe thallium salt reacted with 6.7 g (0.0427 mol) of chloromethyl phenylsulfide in DMF to give 6.85 g (50%) of2-phenylthiomethyl-4-methylsaccharin.

Reaction of the latter (6.7 g, 0.021 mol) with sulfuryl chloride in MDCafforded 4.9 g (95%) of 2-chloromethyl-4-methylsaccharin.

Preparation 14A

A mixture of 75 g (0.36 mol) of 3,3-dithiobispropionic acid, 102 ml ofthionyl chloride and a catalytic amount of pyridine was stirred forabout 24 hours and then evaporated to dryness in vacuo. The residue wastreated with MDC and evaporated to dryness again to remove residualthionyl chloride and pyridine to give 87 g (98%) of the correspondingbis acid chloride, 44.8 g (0.18 mol) of which was dissolved in THF andadded dropwise to a solution of 77.16 g (0.72 mol) of benzylamine in THFThe mixture was stirred for two hours at 40°-45° C. cooled and theprecipitated solid collected, washed with water and dried to give 59 g(84%) of 3,3-dithiobis-propionic acid N,N'-dibenzylcarboxamide, mp162°-165° C.

Reaction of 7.0 g (0. 018 mol) of the latter with 10.25 g (0.076 mol) ofsulfuryl chloride in MDC gave a mixture of 2-benzyl-2H-isothiazol-3-oneand 5-chloro-2-benzyl-2H-isothiazol-3-one which were largely separatedfrom one another by sonication in MDC (which solubilized most of theformer). The insoluble material was collected by filtration andchromatographed on silica gel with MDC. There was thus obtained5-chloro-2-benzyl-2H-isothiazol-3-one, mp 58°-68° C.

A solution of 10 g (0.044 mol) of the latter in MDC was cooled to 0° C.and the solution treated with 7.6 g (0.044 mol) of 3-chloroperbenzoicacid, the mixture stirred for 10 minutes and then treated with a second7.6 g portion of the perbenzoic acid. The reaction mixture was filtered,the filter washed with MDC and the filtrate washed with saturated sodiumbicarbonate, then with brine, dried over sodium sulfate and taken todryness and the residue chromatographed in MDC on silica gel, theproduct being eluted with 50:50 hexane:MDC, to give 7.15 g (46%) of5-chloro-2-benzyl-2H-isothiazol-3-one-1-oxide.

A solution of 1.1 g (0.0045 mol) of the latter in 8 ml of benzene wastreated with 0.55 g (0.0051 mol) of 2-methoxyfuran and the solutionheated in a pressure bottle at 70° C. for 1.5 hours and then cooled andthe solid collected, washed with benzene and dried to give2-benzyl-7-hydroxy-4-methoxybenzisothiaziol-3-one-1-oxide, mp 235°-237°C.

A mixture of the product (1.85 g, 0.006 mol), 2.48 g (0.018 mol) ofpotassium carbonate and 1.70 g (0.012 mol) of methyl iodide in acetonewas heated under reflux for 1.5 hours and then cooled and poured intowater. The solid which separated was collected by filtration, washedwith water and dried to give 1.70 g (89%) of2-benzyl-4,7-dimethoxybenzisothiazol-3-one-1-oxide, 1.13 g (0.0035 mol)of which was oxidized with 1.20 g (0.007 mol) of 3-chloroperbenzoic acidin MDC using the procedure described above to give 1.03 g (88%) of2-benzyl-4,7-dimethoxysaccharin.

A mixture of 2.07 g (0.0062 mol) of the product, 1.37 g (0.02 mol) ofammonium formate and 1.5 g of 10% palladium-on-charcoal catalyst in 80ml of methanol was heated under reflux for one hour, then cooled andfiltered, and the filtrate taken to dryness to give 0.92 g (57%) of theammonium salt of 4,7-dimethoxysaccharin.

A solution of 1.11 g (0.0042 mol) of the ammonium salt was dissolved inDMF, 0.67 g (0.0042 mol) of chloromethyl phenyl sulfide was added, andthe solution heated under reflux for eight hours and then cooled andpoured into ice water. The solid which separated was collected, washedwith water and dried to give 0.50 g (33%) of2-phenylthiomethyl-4,7-dimethoxysaccharin.

Reaction of the latter (0.5 g, 0.0013 mol) with sulfuryl chloride in MDCusing the procedure described above in Preparation 4 afforded 0.22 g(58%) of 2-chloromethyl-4,7-dimethoxysaccharin.

Preparations 14B and 14C

Following a procedure similar to that described in Preparation 14A,other 2-chloromethylsaccharin derivatives were prepared as follows:

Preparation 14B

Reaction of 5.8 g (0.024 mol) of5-chloro-2-benzyl-2H-isothiazol-3-one-1-oxide with 3.76 g (0. 0335 mol)of 2-ethoxyfuran afforded 3.05 g (40%) of2-benzyl-4-ethoxy-7-hydroxybenzisothiazol-3-one-1-oxide, 5.7 g of whichwas reacted with 3.6 g (0.0197 mol) of 2-[2-methoxyethoxy]ethyl bromidein the presence of 4.95 g (0.0358 mol) of potassium carbonate in 125 mlof methyl ethyl ketone and 25 ml of DMF to give 7.0 g (93%) of2-benzyl-4-ethoxy-7-[2-(2-methoxy-ethoxy]-ethoxy]benzisothiazol-3-one-1-oxide,which was oxidized as before with 3-chloroperbenzoic acid in MDC to give2-benzyl-4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]-saccharin. Debenzylationof 6.6 g (0.015 mol) of the latter with 3.34 g (0.053 mol) of ammoniumformate in the presence of 6.4 g of 10% palladium-on-charcoal catalystin methanol afforded the ammonium salt of4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin, which was reacted with2.38 g (0.015 mol) of chloromethyl phenyl sulfide in 100 mL of DMF togive 1.46 g (21%) of2-phenylthiomethyl-4-ethoxy-7-[2-(2-methoxyethoxy]-ethoxy]saccharin, mp73°-75 ° C. (from isopropanol). Treatment of 1.4 g (0.0029 mol) of theproduct with 0.4 g (0.0029 mol) of sulfuryl chloride in MDC afforded1.16 g (100%) of2-chloromethyl-4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]-saccharin.

Preparation 14C

Reaction of 3.03 g (0.01 mol) of2-benzyl-7-hydroxy-4-methoxybenzisothiazol-3-one-1-oxide (Preparation14A) with 2.01 g (0.011 mol) of 2-(2-methoxyethoxy)ethyl bromide inmethyl ethyl ketone in the presence of 2 g (0.015 mol) of potassiumcarbonate afforded 2.58 g (64%) of2-benzyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]benzisothia-zol-3-one-1-oxide,which, on oxidation with 1.1 g (0.0063 mol) of 3-chloroperbenzoic acidin MDC, gave 2-benzyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin.Debenzylation of 0.25 g (0.0006 mol) of the product with 0.13 g (0.0021mol) of ammonium formate in methanol in the presence of 0.25 g of 10%palladium-on-charcoal gave 0.21 g (100%) of the ammonium salt of4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin. Reaction of 1.4 g(0,004 mol) of the ammonium salt with 0.63 g (0,004 mol) of chloromethylphenyl sulfide in DMF afforded2-phenylthiomethyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin,which, on reaction with sulfuryl chloride in MDC, afforded 0.53 g (35%)of 2-chloromethyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin.

Preparation 15

A solution of 1.89 g (0.011 mol) of diethylamino sulfur trifluoride(DAST) in 20 ml of MDC was added to a suspension of 2.13 g (0.01 mol) of2-hydroxymethylsaccharin in 25 ml of MDC while maintaining the reactionmixture at -78° C.

The reaction mixture was stirred at -78° C. for one hour, thetemperature allowed to slowly rise to ambient temperature, the mixturestirred for 16 hours and then poured into ice-water. The organic layerwas separated and washed with water, dried over magnesium sulfate andtaken to dryness to give 2.2 g of product which was recrystallized fromethyl acetate to give 1.6 g (74%) of 2-fluoromethylsaccharin, mp 96°-98°C.

Preparation 16A

To a solution of 0.5 g (0.0025 mol) of 4-methylsaccharin in THF cooledto -78° C. by a dry ice/acetone bath was added, dropwise with stirring,a solution of 5.2 ml of a 1.3M solution of s-butyl lithium incyclohexane. The mixture was stirred an additional hour at -78° C. andthen treated with 0.16 ml (0.025 mol) of methyl iodide over a 11/2 hourperiod. The mixture was stirred for an hour and 45 minutes, quenched in25 ml of 1N hydrochloric acid, the reaction mixture rendered basic, theaqueous mixture extracted with chloroform and then acidified andextracted with ethyl acetate. The combined organic extracts were washedwith 10% sodium thiosulfate, then with brine, dried over sodium sulfateand taken to dryness to give a product, whose PMR spectrum indicated amixture consisting of 74% of 4-ethylsaccharin and 21% of4,7-dimethylsaccharin.

Following a procedure similar to that described in Preparation 4 above,the crude material (0.47 g, 0.0022 mol) was reacted with 0.24 ml (0.0028mol) of chloromethyl phenylsulfide in toluene in the presence oftetrabutylammonium bromide, and the product chromatographed on silicagel, eluting with MDC, 5 ml fractions being collected. The first 420 mlof eluate were discarded. The next 20 fractions, on evaporation,afforded 0.07 g of material, predominantly2-phenylthiomethyl-4,7-dimethylsaccharin, which was set aside. The next25 fractions afforded 0.37 g of 2-phenylthiomethyl-4-ethylsaccharin,which was reacted with sulfuryl chloride in MDC to give 0.19 g (66%) of2-chloromethyl-4-ethylsaccharin.

Preparation 16B

Following a procedure similar to that described in Preparation 16A, 10 g(0.051 mol) of 4-methylsaccharin in THF was reacted with 86 ml (0.10mol) of a 1.18M solution of s-butyl lithium in cyclohexane and theresulting solution treated with 4.5 ml (0.050 mol) of ethyl iodide togive 10.15 g (89%) of 4-propylsaccharin, which, on reaction with 5.32 ml(0.056 mol) of chloromethyl phenyl sulfide in toluene in the presence oftetrabutylammonium bromide, afforded a crude mixture from which wasisolated by flash chromatography on silica gel2-phenylthiomethyl-4-propylsaccharin as an oil, 1.8 g (0.0052 mol) ofwhich, on reaction with 1.25 ml (0.016 mol) of sulfuryl chloride in MDC,afforded 0.94 g (66%) of 2-chloromethyl-4-propylsaccharin.

Preparation 16C

A preferred alternative to preparation 16A is as follows:

To a solution of 5.13 g (25 mmol) of N,N,2-triethylbenzamide in THF (50mL) at -78° C. was added a solution of LDA (Aldrich 2.0M, 15.63 mL,31.25 mmol). The solution was warmed to -10° C. with ice water over 1hr, then cooled to -78° C. with dry ice-acetone. TMSCl (6.34 mL, 50mmol) was added neat at -78° C. and then reaction brought to roomtemperature after 1 hr. The reaction was quenched with saturated NH₄ Cland extracted with ether (2×100 mL), dried over MgSO₄, stripped and theresidue distilled in a Kugelrohr (130°-140° C., 0.65 mm) to obtain 6.51g (94%) of N,N-diethyl-2-[1-(trimethylsilyl)ethyl]benzamide.

To a solution of sec-BuLi (0.97M, 5.10 mL, 4.96 mmol) and TMEDA (0.75mL, 4.96 mmol) in THF at -78° C. was added the amide (1.25 g, 4.50 mmol)in THF. Excess SO₂ in THF was added quickly at -78° C. then warmed toroom temperature. The THF was removed in vacuo and the residue treatedat 0° C. with two equivalents of a 1:1 solution of sodium hydroxide(0.36 g, 9.0 mmol) and hydroxylamine-O-sulfonic acid (1.0 g, 9.0 mmol)in H₂ O. The reaction was stirred at room temperature for 4 hrs,extracted with EtOAc, dried over MgSO₄, concentrated and flashchromatographed on silica gel with 20% ethyl acetate/hexane to give 0.62g (41%) of2-aminosulfonyl-N,N-diethyl-6-[1-(trimethylsilyl)-ethyl]benzamide. Thebenzamide (0.95 g, 2.66 mol) was refluxed in glacial acetic acid (20 mL)for 18 hr, stripped to dryness, triturated with hot cyclohexane (30 mL)and a trace of EtOAc (3 mL), cooled with scratching and filtered. Therewas obtained 0.81 g (85%) of 4-[1-(trimethylsilyl)-ethyl]saccharin, mp123°-125° C.

To the trimethylsilylethylsaccharin (0.25 g, 0.70 mmol) in DMF (9 mL) atroom temperature was added H₂ O (1 mL) and cesium fluoride (0.75g ,4.94mmol, 7 equivalents). After 7 hr the reaction was poured into 5% NaOHand extracted with EtOAc. The aqueous layer was acidified with 12N HCland extracted with Et₂ O -EtOAc (1:1), dried over Na₂ SO₄, filtered andstripped to give a colorless solid in quantitative yield. It wasrecrystallized from 5% Et₂ O-hexanes to give 0.091 g (64%) of4-ethylsaccharin, mp 183° 185° C.

Preparation 17

The 0.07 g sample of material obtained in the early fractions from thechromatographic separation described above in Preparation 16A consistingpredominantly of 2-phenylthiomethyl-4,7-dimethylsaccharin was reactedwith 0.05 ml of sulfuryl chloride in MDC and the product recrystallizedfrom cyclohexane-ethyl acetate to give 20 mg (51%) of2-chloromethyl-4,7-dimethylsaccharin, mp 107°-108° C.

Preparation 18A

To a solution of 40.0 g (0.174 mol) of 2-isopropyl-4-methoxybromobenzenein 600 ml of diethyl ether at 0° C. was added 103.68 ml (0.175 mol) of a1.69M solution of butyl lithium in diethyl ether. When the addition wascomplete the solution was cooled to 0° C. for one hour and stirred foran additional five hours at ambient temperature, then recooled to -78°C. and treated with a solution of 23.68 g (0.175 mol) ofN,N-diethylcarbamyl chloride in 80 ml of diethyl ether. The resultingsolution was stirred for about 12 hours while the reaction temperaturewas allowed to rise and then quenched with saturated ammonium chloridesolution. The aqueous and organic layers were separated, the aqueouslayer back extracted with ethyl acetate and the combined organicextracts washed once with brine, then dried and the solution taken todryness to give a crude product which was flash chromatographed onsilica gel, eluting with 30% ethyl acetate/hexane to give 34.4 g (79%)of 2-isopropyl-4-methoxy-N,N-diethylbenzamide as an oil which was usedas such in the next step without further purification. The oil can bedistilled, if desired, and boils at 123°-129/0.2-0.3 min.

Following a procedure similar to that described in Preparation 5 above,the latter (15.0 g, 0.060 mol) in 100 ml of diethyl ether was reactedwith 77.8 ml (0.784 mol) of a 1.2M solution of s-butyl lithium incyclohexane in the presence of 6.98 g (0.06 mol) oftetramethylethylenediamine. The resulting lithium salt was then reactedfirst with 50 ml of sulfur dioxide and then with 0.181 mol of sodiumhydroxylamine-O-sulfonate to give 11.6 g (59%) of2-aminosulfonyl-6-isopropyl-4-methoxy-N,N-diethylbenzamide, m.p.103°-105° C. (from ethyl acetate/hexane). Eleven grams (0.034 mol) ofthe benzamide was cyclized in 200 ml of refluxing glacial acetic acid togive 10.3 g of the diethylammonium salt of4-isopropyl-6-methoxysaccharin, m.p. 132°-135° C.

The latter (0.030 mol), on reaction with 6.14 ml (7.25 g, 0.046 mol) ofchloromethyl phenyl sulfide in the presence of 0.98 g. (0.003 mol) ofTBAB in 250 ml of toluene, afforded 10.1 g (88%) of2-phenylthiomethyl-4-isopropyl-6-methoxysaccharin as an oil, 9.7 g(0.026 mol) of which, on reaction with 3.1 ml (5.21 g, 0.039 mol) ofsulfuryl chloride in MDC, afforded 6.9 g (88% of2-chloromethyl-4-isopropyl-6-methoxysaccharin, mp 151°-152° C.

Preparation 18B

An alternative procedure was also followed:

To a solution of 300 mL of N,N,N',N'-tetramethylethylenediamine (TMEDA)(1.99 moles) in 4L of anhydrous ether was added 1550 mL of sec-BuLi(1.3M) and the system was cooled to -70° C. under a nitrogen atmosphere.A solution of 454.2 g of 2-isopropyl-4-methoxy N,N-diethylbenzamide(1.82 moles) in 300 mL of anhydrous ether was added dropwise over 30minutes (the temperature was maintained at or below -60° C. during theaddition). After the addition was complete, the reaction was stirred at-70° C. for one hour and allowed to warm to -50° C. After holding thetemperature at -50° C. for 30 minutes, the mixture was cooled back to-70° C. To this stirred solution was added via cannulating tube asolution of 200 g of SO₂ in 200 mL of dry ether precooled to -40° C.under positive nitrogen pressure over a 20-minute period. Thetemperature of the reaction mixture during the addition was maintainedbelow -40° C. (A white powdery precipitate of aryllithium sulphinateseparated out almost immediately). After the addition, the ice-bath wasremoved and the reaction was allowed to stir at ambient temperature fortwo hours. It was cooled to -5° C. and to this stirred solution wasadded 190 ml of sulfuryl chloride (2.36 moles) dropwise over a 15-minuteperiod maintaining the temperature below 10° C. during the additionAfter further stirring for 30 minutes at 0°-5° C., a white insolubleprecipitate was filtered off and washed with 2L of anhydrous ether.Removal of the solvent at atmospheric pressure afforded the sulfonylchloride as a crude dark oil. This crude sulfonyl chloride was dissolvedin 1.4L of THF, cooled to -10° C. and 540 mL of concentrated NH₄ OH(28%) was added in portions over 15 minutes (the temperature was kept at15° C. or below throughout the addition). After stirring for 15 minutesat ambient temperature, the THF and excess ammonia were removed undervacuum to give a dark oil, which was diluted with 6.0L of water andacidified with 3N HCl to pH 1. The light yellow solid was collected byfiltration and washed with 800 mL of water. The solid was dried at 60°C. under vacuum for 18 hours and recrystallized from a mixture of 800 mLof ethyl acetate and 3L of hexane to give 429 g (72%) of2-aminosulfonyl-6-isopropyl-4-methoxy-N,N-diethylbenzamide, mp 122°-125°C.

A solution of 429.6 g of the diethylbenzamide (1.31 mole) in 1.5L ofacetic acid was refluxed for 20 hours. It was cooled to room temperatureand the solvent removed under vacuum. The oily residue was dissolved in6L of water and adjusted to pH 1 with 6N HCl. The crude product wascollected by filtration and washed with 2L of water. The solid was driedat 60° C. under vacuum for 18 hours and recrystallized from ethylacetate/hexane to give 303 g (91%) 4-isopropyl-6-methoxysaccharin, mp188° C.

To a suspension of 24 g of paraformaldehyde (0.8 mole) and 86.4 g ofchlorotrimethylsilane (1.6 moles) in 200 mL of 1,2-dichloroethane wasadded 0.8 ml anhydrous tin(IV) chloride and the resulting solutionstirred on a steam bath for one hour. At the end of this period, 51 g of4-isopropyl-6-methoxysaccharin (0.2 mole) was added to the clearsolution and the reaction mixture was further refluxed for 18 hours. Itwas cooled to room temperature, poured into water, the organic layerseparated and washed with 50 mL of 2N sodium hydroxide solution. Theorganic layer was dried over anhydrous magnesium sulfate andconcentrated under vacuum to give crude product. It was purified bycrystallization from ethyl acetate/hexane to give 57 g (87%) of2-chloromethyl-4-isopropyl-6-methoxysaccharin, mp 151° C.

Preparation 18C

Following the procedure of preparation 18A, 5 g of2-bromo-N,N-dimethylaniline was converted to 3.5 g ofN,N-diethyl-2-dimethylaminobenzamide. The amide was reacted by themethod of preparation 18B to provide 65 mg of 4-dimethylaminosaccharin,which can be converted into 2-chloromethyl-4-dimethylaminosaccharin asshown in preparation 23V.

Preparation 19

To a solution of 1.0 g (0.0039 mol) of 4-isopropyl-6-methoxysaccharin in15 ml of MDC was added at ambient temperature 1.28 g (5.12 ml) of a 1Msolution of boron tribromide in MDC. When addition was complete thereaction mixture was heated under reflux for about five hours, cooled,taken to dryness in vacuo and the residue treated with ice and saturatedsodium bicarbonate. The aqueous solution was extracted once with ethylacetate and then acidified to pH 1 with concentrated hydrochloric acid.Extraction of the mixture with ethyl acetate/diethyl ether (8:2), dryingthe organic extracts and removal of the solvent in vacuo afforded 0.9 g(96%) of 6-hydroxy-4-isopropylsaccharin as a white crystalline solidwhich was used as such in the next step.

An alternative procedure was also used. To a stirred suspension of 62.74g (0.47 mol) of AlCl₃ in 500 mL of chloroform at 0° was added 43.9 g(0.7 mol) of ethanethiol. Within minutes a clear solution formed. Tothis a solution of 20.0 g (0.078 mol) of 4-isopropyl-6-methoxysaccharinin 550 mL of chloroform was added over a 30-min period. This solutionwas allowed to warm to RT and stirred for 3-4 hr at 60°. After cooling,the mixture was poured into ice-water and acidified with dilute HCl. Thesolid which separated was collected by filtration, washed with water anddried to give 18.4 g (97%) of 6-hydroxy-4-isopropylsaccharin.

Following a procedure similar to that described in Preparation 4 above,the latter (0.004 mol) was reacted with 0.61 ml (0.0046 mol) ofchloromethyl phenyl sulfide in toluene in the presence of 0.133 g (0.004mol) of TBAB to give 0.32 g (21%) of4-isopropyl-6-hydroxy-2-phenylthio-methylsaccharin, m.p. 127-129.5, 1.78g of which was treated with 0.43 ml (0.73 g) of sulfuryl chloride in MDCto give 1.2 g (84%) of 2-chloromethyl-4-isopropyl-6-hydroxy-saccharin,m.p. 149°-150° C.

Preparation 19A

Following a procedure substantially similar to that described inpreparation 19 but substituting 4-methoxysaccharin for4-isopropyl-6-methoxysaccharin it is contemplated that2-chloromethyl-4-hydroxysaccharin can be prepared.

Preparation 20

Five grams (0.0207 mol) of 6-hydroxy-4-isopropylsaccharin was dissolvedin 150 ml of methanol and 3.4 g (0.0104 mol) of Cs₂ CO₃ was added. Themixture was stirred for 3-4 hr at RT. The excess methanol was removedunder reduced pressure and the residue was dried for 2 hr under highvacuum. The residue was then dissolved in 110 mL of DMF and 0.32 g(0.0209 mol) of chloromethyl phenyl sulfide was added. The stirredmixture was heated at 70°-75° for 12 hr, cooled, treated with ice waterand extracted with 600 mL of 4:1 ethyl acetate:ether. The organic layerwas washed with water and saturated NaCl and dried. The solvent wasremoved under reduced pressure. The residue was purified by flashchromatography with 20% ethyl acetate in MDC. There was obtained 4.5 g(60%) of 4-isopropyl-6-hydroxy-2-phenylthio-methylsaccharin, mp150°-151.5° C. which, on reaction with sulfuryl chloride as described inPreparation 19, yielded 2-chloromethyl-4-isopropyl-6-hydroxysaccharin asbefore.

Preparation 21

To a solution of 5-chloro-2-benzyl-4-isothiazolin-3-one (J. Het. Chem.8, 571, 1971) (9.4 g, 0.04 mol) in MDC (100 mL) was added in one portion80-85% 3-chloroperoxy-benzoic acid (10.8 g, 0.06 mol) and the resultingmixture stirred at room temperature overnight under nitrogen. Theprecipitated solids were filtered off and washed with MDC (50 mL). Thecombined filtrate was evaporated to near dryness and the residuepartitioned between ethyl acetate (300 mL) and saturated NaHCO₃ (100mL). The layers were separated and the organic phase washed withsaturated NaHCO₃ (2×100 mL), brine (1×100 mL) and dried. Removal of thesolvent in vacuo afforded 10.0 g (99%) of5-chloro-2-benzyl-4-isothiazolin-3(2H)-one 1-oxide as a pale yellow oil.

The 1-oxide (10.0 g, 0.04 mol) in glacial acetic acid (200 mL) wastreated with 30% H₂ O₂ (100 mL, 0.88 mol) and heated on a steam bath for2 hr during which time an additional 30 mL (0.26 mol) of 30% H₂ O₂ wasadded. After heating on a steam bath for an additional hour, thereaction mixture was cooled to room temperature and poured into ice coldwater (1L) and stirred. The precipitated solids were collected byfiltration, washed with water (2×100 mL), hexanes and air dried to give4.8 g (45%) of 5-chloro-2-benzyl-4-isothiazolin-3(2H)-one 1.1-dioxide asa colorless solid.

The dioxide (1.2 g 4.7 mmol) was mixed with 2.02 (11 mmol) of2-trimethylsiloxy-5-methyl-hexa-1,3-diene (prepared from5-methyl-hex-3-ene according to the method of E. J. Corey et al., Tet.Lett. 495, 1984) in toluene (50 mL) and refluxed for a period of 20 hrunder nitrogen. The resulting mixture was cooled to room temperature andconcentrated in vacuo. The residue was dissolved in THF (25 mL) andtreated with 2N HCl (10 mL). After stirring under nitrogen at roomtemperature for 10 min, ether (100 mL) was added and the layersseparated. The organic phase was washed with water, brine, dried andevaporated to dryness to give a pale yellow foam. The foam was dissolvedin toluene (30 mL), DBN (1.5 mL) was added and stirred at roomtemperature for 2 hr. MDC (100 mL) and 2N HCl (50 mL) were added andstirring continued for 5 min. The layers were separated and the organicphase washed with water, brine and dried. Removal of the solvent invacuo and purification of the residue by flash chromatography on silicagel (5:4:1, hexanes:MDC:ether) gave 0.6 g (39%) of2-benzyl-4-isopropyl-6-oxo-tetrahydro saccharin as a pale yellow foam.

The tetrahydrosaccharin (0.59 g, 1.7 mmol) was dissolved in toluene (50mL), dimethylamine hydrochloride (1.5 g, 18.0 mmol) and 4 A sieves (2.0g) were added. The resulting mixture was refluxed with azeotropicremoval of water for 96 hr. It was necessary to add additionaldimethylamine hydrochloride (0.8 g, 10.0 mmol) and 4 A sieves every 12hr during this 96 hr period at the end of which time, the reactionmixture was cooled to room temperature and filtered. The filter cake waswashed with diethyl ether (100 mL) and the combined filtrates wereconcentrated in vacuo to give 0.63 g (99%) of2-benzyl-4-isopropyl-6-dimethylamino-(4,5)dihydrosaccharin as a paleyellow solid.

To a solution of the dihydrosaccharin (0.63 g, 1.7 mmol) in refluxingchloroform (50 mL) was added activated manganese dioxide (4.3 g, 49.5mmol) in portions over a period of 4 hr. After the addition of the lastportion of manganese dioxide, the reaction was refluxed for anadditional hr, cooled to room temperature and filtered through a pad ofsuper cel, eluting with ethyl acetate. The combined eluents wereconcentrated in vacuo and the residue purified by flash chromatographyon silica gel (5:4:1, hexanes:MDC:ether) to give 0.32 g (50%) of2-benzyl-4-isopropyl-6-dimethylaminosaccharin as a colorless solid.

The 2-benzylsaccharin (0.32 g, 0.9 mmol) in methanol (20 mL) was treatedwith ammonium formate (0.24 g, 3.8 mmol) and 10% Pd on Carbon (0.25 g)and refluxed for 1 hr, cooled to room temperature and filtered through apad of super cel, eluting with methanol (100 mL). The combined eluentswere concentrated in vacuo. The residue was dissolved in MDC (10 mL),glacial acetic acid (0.25 mL) was added, stirred for 5 min. andevaporated to dryness in vacuo to give 0.25 g (100%) of4-isopropyl-6-dimethylamino-saccharin as a colorless foam.

Following a procedure similar to that described in Preparation 1, amixture of 4-isopropyl-6-dimethylamino-saccharin (0.27 g, 1.0 mmol),chloromethyl phenylsulfide (0.32 g, 2.0 mmol) and tetrabutyl ammoniumbromide (0.1 g, 0.2 mmol) in toluene was converted to 0.22 g (56%) of2-phenylthiomethyl-4-isopropyl-6-dimethylamino-saccharin which wastreated with sulfuryl chloride (1.86 mL of 0.31M solution, 0.6 mmol) togive 0.15 g of a yellow gum that contained 25% (by NMR) of2-chloromethyl-4-isopropyl-6-dimethylamino-7-chloro saccharin.

Preparation 22A

Thirty-one grams of 4-isopropyl-1,2-dimethoxybenzene was treated withN-bromosuccinimide followed by butyllithium and diethyl carbamylchloride as in preparation 6B to yield 15.2 g of2-isopropyl-4,5-dimethoxy-N,N-diethylbenzamide as a viscous oil. Thebenzamide was treated according to preparation 18B with butyllithium andsulfur dioxide followed by sulfuryl chloride then ammonia to provide 4.5g of the sulfonamide, mp 181°-182° C. from ether. This was cyclized inacetic acid as in preparation 18B to obtain 2.86 g of6,7-dimethoxy-4-isopropylsaccharin, mp 210°-212° C. from ethylacetate-hexane.

To a solution of 0.5 g of 4-isopropyl-6,7-dimethoxysaccharin in 3 mL ofDMF was added 0.5 mL of diisopropylethylamine at room temperature. After15 min, 0.35 g chloromethyl phenyl sulfide was added and the mixtureheated at 80° C. for 16 hrs. The reaction mixture was poured into EtOAcand washed with aqueous Na₂ CO₃ solution, aqueous 2N HCl solution,saturated aqueous NaCl solution. The organic layer was dried over Na₂SO₄ and the solvents removed. Chromatography with MDC gave 0.35 g ofdesired product, which was used immediately. Treatment of the 0.35 gsample of phenylthiomethyl saccharin in 3 mL of MDC with 0.1 mL ofsulfuryl chloride for 30 min at 20° followed by removal of solvents andtrituration with hexane gave 0.3 g of2-chloromethyl-6,7-dimethoxy-4-isopropylsaccharin.

Preparation 22B

To a solution of 5.7 g of methyl piperonylate in 20 mL of dry ether wasadded 30 mL of 3.0 methyl magnesium bromide in ether at 0° C. over 20min. The mixture was stirred for 20 hrs then diluted with 200 mL ofether and washed with water. The organic layer was dried with Na₂ SO₄and the solvents removed to yield 5.6 g of crude3,4-dimethoxy-(1'-hydroxy-1'-methylethyl)benzene. This material wasimmediately treated in 50 mL of acetic acid with 1 g of 10% Pd/C under50 psi of hydrogen for 20 hrs. Filtration to remove catalyst and removalof solvent yielded 4.5 g of 5-isopropyl-1,3-benzodioxole. Theisopropyldioxole was brominated, amidated, sulfonated and cyclized as in22A to yield 700 mg of 4-isopropyl-6,7-methylenedloxysaccharin, mp226°-228° from ethyl acetate/hexane. Five hundred milligrams of thesaccharin was chloromethylated as in 22A to provide 300 mg of2-chloromethyl-4-isopropyl-6,7-methylenedioxysaccharin. mp 174°-176°.

Other 4-R⁴ -R⁵ -saccharins of formula II useful as intermediates for thepreparation of the compounds of formula I can be prepared as follows.

Reaction of 2-trifluoromethylbenzoic acid with thionyl chloride affords2-trifluoromethylbenzoyl chloride, which, on reaction with diethylamine,affords 2-trifluoro-methyl-N,N-diethylbenzamide. Following a proceduresimilar to that described in Preparation 5, reaction of the latter withs-butyl lithium and reaction of the resulting lithium salt with sulfurdioxide followed by sodium hydroxylamine-O-sulfonate affords2-trifluoromethyl-6-aminosulfonyl-N,N-diethylbenzamide, which, onheating in glacial acetic acid, affords 4-trifluoromethylsaccharin.

Similarly, reaction of 2-trichloromethylbenzoic-acid with thionylchloride affords 2-trichloromethylbenzoyl-chloride, which, on reactionwith diethylamine, affords 2-trichloromethyl-N,N-diethylbenzamide.Following a procedure similar to that described in Preparation 5,reaction of the latter with s-butyl lithium and reaction of theresulting lithium salt with sulfur dioxide followed by sodiumhydroxyl-amine-O-sulfonate affords2-trichloromethyl-6-aminosulfonyl-N,N-diethylbenzamide, which, onheating in glacial acetic acid, affords 4-trichloromethylsaccharin.

Reaction of 4-cyclohexylbenzoic acid with thionylchloride affords4-cyclohexylbenzoyl chloride, which, on reaction with diethylamine,affords 4-cyclohexyl-N,N-diethylbenzamide. Following a procedure similarto that described in Preparation 5, reaction of the latter with s-butyllithium and reaction of the resulting lithium salt with sulfur dioxidefollowed by sodium hydroxylamine-O-sulfonate affords4-cyclohexyl-2-aminosulfonyl-N,N-diethylbenzamide, which, on heating inglacial acetic acid, affords 6-cyclohexyl saccharin.

Benzylation of 6-nitrosaccharin affords 2-benzyl-6-nitrosaccharin whichon reduction with stannous chloride and aqueous hydrogen chlorideaffords 2-benzyl-6-aminosaccharin. Reaction of the latter withmethanesulfonyl chloride, trifluoromethylsulfonyl chloride ortrichloro-methylsulfonyl chloride in MDC in the presence of pyridinefollowed by transfer hydrogenolysis of the 2-benzyl protecting group,affords, respectively, 6-methyl-sulfonylaminosaccharin,6-trifluoromethylsulfonyl-aminosaccharin or6-trichloromethyl-sulfonylaminosaccharin.

Diazotization of 6-aminosaccharin with nitrous acid in an acid mediumand decomposition of the resulting diazonium salt in the presence ofcuptic cyanide or cupric chloride and sulfur dioxide, or cupric chlorideand an alkali metal salt of methyl mercaptan or trifluoromethylmercaptan affords, respectively, 6-cyanosaccharin,6-chlorosulfonylsaccharin, 6-methylthiosaccharin or6-trifluoromethylthiosaccharin. Reaction of the6-chlorosulfonylsaccharin in situ with ammonia or methanesulfonyl-amideaffords, respectively, 6-aminosulfonylsaccharin and6-methane-sulfonylaminosulfonylsacchaarin. Oxidation of6-methylthiosaccharin and 6-trifluoromethylthiosaccharin with two molarequivalents of 3-chloroperbenzoic acid affords 6-methylsulfonylsaccharinand 6-trifluoromethylsulfonylsaccharin, respectively.

Hydrolysis of 6-cyanosaccharin by heating with aqueous sodium hydroxideaffords saccharin-6-carboxylic acid. N-benzylation of 6-cyanosaccharinaffords 2-benzyl-6-cyanosaccharin. The latter on alkaline hydrolysisaffords 2-benzylsaccharin-6-carboxylic acid which on conversion to2-benzylsaccharin-6-carboxylic acid chloride by reaction with thionylchloride followed by exhaustive hydrogenation over palladium-carbonaffords 6-hydroxymethylsaccharin. Oxidation of the latter withpyridine:chromium trioxide (2:1) complex (Collins reagent) in MDCaffords 6-formyl-saccharin, which, on reductive amination with ammoniaaffords 6-aminomethylsaccharin.

Reaction of 4-trifluoromethylbenzoic acid with thionyl chloride affords4-trifluoromethylbenzoyl chloride, which, on reaction with diethylamine,affords 4-trifluoro-methyl-N,N-diethylbenzamide. Following a proceduresimilar to that described in Preparation 5, reaction of the latter withs-butyl lithium and reaction of the resulting lithium salt with sulfurdioxide followed by sodium hydroxylamine-O-sulfonate affords4-trifluoromethyl-2-aminosulfonyl-N,N-diethylbenzamide, which on heatingin glacial acetic acid, affords 6-trifluoro-methylsaccharin.

Reaction of 4-trichloromethylbenzoic acid with thionyl chloride affords4-trichloromethylbenzoyl chloride, which, on reaction with diethylamine,affords 4-trichloro-methyl-N,N-diethylbenzamide. Following a proceduresimilar to that described in Preparation 5, reaction of the latter withs-butyl 10 lithium and reaction of the resulting lithium salt withsulfur dioxide followed by sodium hydroxylamine-O-sulfonate affords4-trichloromethyl-2-aminosulfonyl-N,N-diethylbenzamide, which, onheating in glacial acetic acid, affords 6-trichloromethylsaccharin.

Reaction of 2-ethenylbenzoic acid with thionyl chloride affords2-ethenylbenzoyl chloride, which on reaction with diethylamine, affords2-ethenyl-N,N-diethylbenzamide. Reaction of the latter with s-butyllithium and reaction of the resulting lithium salt with sulfur dioxidefollowed by sodium hydroxylamine-O-sulfonate affords2-ethenyl-6-aminosulfonyl-N,N-diethylbenzamide, which, on heating inglacial acetic acid, affords 4-ethenylsaccharin.

Reaction of 2-ethenyl-6-aminosulfonyl-N,N-diethylbenzamide with bromineaffords 2-(1,2-dibromoethyl)-6-aminosulfonyl-N,N-diethylbenzamide which,on reaction with sodium amide in ammonia affords2-ethynyl-6-aminosulfonyl-N,N-diethylbenzamide, which, on heating inglacial acetic acid, affords 4-ethynylsaccharin.

Reaction of ethyl 2-aminobenzoate with two molar equivalents of benzylChloride in acetone in the presence of potassium carbonate affords ethyl2-(N,N-dibenzylamino)-benzoate which, on saponification in aqueousethanolic potassium hydroxide and isolation of the product from aneutral medium, affords 2-(N,N-dibenzylamino)benzoic acid.

Reaction of the latter with thionyl chloride affords2-(N,N-dibenzylamino)benzoyl chloride, which, on reaction withdiethylamine, affords 2-(N,N-dibenzylamino)-N,N-diethyl-benzamide.Reaction of the latter with s-butyl lithium and reaction of theresulting lithium salt with sulfur dioxide followed by sodiumhydroxylamine-O-sulfonate affords2-(N,N-dibenzyl)-6-aminosulfonyl-N,N-diethyl-benzamide, which, onheating in glacial acetic acid, affords 4-N,N-dibenzyl-amino)saccharinwhich, on catalytic debenzylation with hydrogen overpalladium-on-charcoal, affords 4-amino-saccharin. Reductive alkylationof the latter with one molar equivalent of formaldehyde in formic acidaffords 4-methylaminosaccharin. Diazotization of 4-aminosaccharin withnitrous acid in an acid medium and decomposition of the resultingdiazonium salt in the presence of cuptic cyanide affords4-cyanosaccharin.

Selective N-benzylation of the cesium salt of4-isopropyl-6-hydroxysaccharin (Preparation 19) with benzyl bromide andreaction of the 2-benzyl-4-isopropyl-6-hydroxysaccharin withN,N-diethylthiocarbamyl chloride in DMF using the procedure describedabove in Preparation 12 affords2-benzyl-4-isopropyl-6-(N,N-diethylthiocarbamyloxy)saccharin which, onheating, rearranges to2-benzyl-4-isopropyl-6-(N,N-diethylcarbamyl-thio)saccharin. The latter,on hydrolysis with alkali, affords2-benzyl-4-isopropyl-6-mercaptosaccharin which on reaction with methyliodide, and transfer hydrogenolysis affords4-isopropyl-6-methylthiosaccharin. Oxidation of the latter with one ortwo molar equivalents of 3-chloroperbenzoic acid affords4-isopropyl-6-methyl-sulfinylsaccharin and4-isopropyl-6-methulsulfonyl-saccharin.

Reaction of 2-isopropyl-4-fluorobenzoic acid with thionyl chlorideaffords 2-isopropyl-4-fluorobenzoyl-chloride, which, on reaction withdiethylamine, affords 2-isopropyl-4-fluoro-N,N-diethylbenzamide.Reaction of the latter with s-butyl lithium and reaction of theresulting lithium salt with sulfur dioxide followed by sodiumhydroxylamine-O-sulfonate affords2-isopropyl-4-fluoro-6-aminosulfonyl-N,N-diethylbenzamide, which, onheating in glacial acetic acid, affords 4-isopropyl-6-fluorosaccharin.

Reaction of the latter with thiophenol, 4-methylphenylthiophenol,4-methoxyphenylthiophenol, 4-chlorophenylthiophenol,1-mercapto-4-methylnaphthalene or 1-mercaptonaphthalene by heating thereactants in DMF affords, respectively,4-isopropyl-6-phenylthiosaccharin,4-isopropyl-6-(4-methylphenylthio)saccharin,4-isopropyl-6-(4-methoxyphenylthio)saccharin,4-isopropyl-6-(4-chloro-phenylthio)-saccharin,4-isopropyl-6-(4-methyl-1-naphthylthio) saccharin and4-isopropyl-6-(1-naphthylthio)saccharin. Oxidation of the latter withone or two molar equivalents of 3-chloroperbenzoic acid affords4-isopropyl-6-phenylsul-finylsaccharin,4-isopropyl-6-phenyl-sulfonylsaccharin,4-isopropyl-6-(4-methylphenylsulfinyl)saccharin,4-isopropyl-6-(4-methylphenylsulfonyl)saccharin,4-isopropyl-6-(4-methoxyphenylsulfinyl)saccharin,4-isopropyl-6-(4-methoxyphenylsulfonyl)saccharin,4-iso-propyl-6-(4-chlorophenylsulfinyl)saccharin,4-isopropyl-6-(4-chlorophenylsulfonyl)saccharin,4-isopropyl-6-(4-methyl-1-naphthylsulfinyl)saccharin,4-isopropyl-6-(4-methyl-1-naphthylsulfonyl)saccharin,4-isopropyl-6-(1-naphthyl-sulfinyl)saccharin and4-isopropyl-6-(1-naphthylsulfonyl)-saccharin.

Reaction of 2-benzyl-4-isopropyl-6-hydroxysaccharin with one molarequivalent of acetic anhydride, benzoyl chloride or 1-naphthylcarboxylic acid chloride followed in each case by transferhydrogenolysis affords, respectively, 4-isopropyl-6-acetoxy-saccharin,4-isopropyl-6-benzoyloxysaccharin and4-isopropyl-6-(1-naphthylcarbonyloxy)saccharin.

Heating 4-isopropyl-6-fluorosaccharin in DMF with azetidine,pyrrolidine, piperidine, morpholine, 1-benzylpiperazine,1-methylpiperazine, imidazole, t-butyl alpha-aminoacetate or ammoniaaffords, respectively, 4-isopropyl-6-(1-azetidinyl)saccharin,4-isopropyl-6-(1-pyrrolidinyl)-saccharin,4-isopropyl-6-(1-piperidinyl)saccharin,4-isopropyl-6-morpholinyl)saccharin,4-isopropyl-6-(4-benzyl-1-piperazinyl]saccharin,4-isopropyl-6-(4-methyl-1-piperazinyl)saccharin,4-isopropyl-6-(1-1H-imidazolyl)-saccharin,4-isopropyl-6-(carbo-t-butoxymethylamino)-saccharin and4-isopropyl-6-aminosaccharin.

Catalytic debenzylation of4-isopropyl-6-(4-benzyl-1-piperazinyl)saccharin with hydrogen overpalladium on charcoal affords 4-isopropyl-6-(1-piperazinyl)saccharin.

Hydrolysis of4-isopropyl-6-(carbo-t-butoxy-carbonylmethylamino)saccharin with dilutehydrochloric acid and isolation of the product from a neutral mediumaffords 4-isopropyl-6-carboxymethylaminosaccharin.

Reaction of 4-isopropyl-6-aminosaccharin with one molar equivalent ofacetyl chloride affords 4-isopropyl-6-acetylaminosaccharin.

Saponification of 4-carbomethoxysaccharin (Preparation 9D) to thecorresponding saccharin-4-carboxylic acid by alkaline hydrolysis,conversion of the acid to the corresponding acid chloride by reaction ofthe acid with thionyl chloride and reaction of the acid chloride withammonia affords saccharin-4-carboxamide.

Reaction of each of the 4-R⁴ -R⁵ -saccharins so-prepared withparaformaldehyde and chlorotrimethylsilane in the presence of stannicchloride in ethylene dichloride affords the 4-R⁴ -R⁵-2-chloro-methylsaccharins of formula IV listed in TABLE B where, ineach instance, X is Cl.

                  TABLE B                                                         ______________________________________                                        Preparation                                                                              R.sup.4   R.sup.5                                                  ______________________________________                                        23A        CF.sub.3  H                                                        23B        CCl.sub.3 H                                                        23C        H         6-cyclohexyl                                             23D        H         6-CH.sub.3 SO.sub.2 NH                                   23E        H         6-CF.sub.3 SO.sub.2 NH                                   23F        H         6-CCl.sub.3 SO.sub.2 NH                                  23G        H         6-CN                                                     23H        H         6-NH.sub.2 SO.sub.2                                      23I        H         6-CH.sub.3 SO.sub.2 NHSO.sub.2                           23J        H         6-CH.sub.3 SO.sub.2                                      23K        H         6-CF.sub.3 SO.sub.2                                      23L        H         6-HOOC                                                   23M        H         6-HOCH.sub.2                                             23N        H         6-OHC                                                    23-O       H         6-NH.sub.2 CH.sub.2                                      23P        H         6-CF.sub.3                                               23Q        H         6-CCl.sub.3                                              23R        CH═CH.sub.2                                                                         H                                                        23S        C.tbd.CH  H                                                        23T        NH.sub.2  H                                                        23U        CH.sub.3 NH                                                                             H                                                        23V        (CH.sub.3).sub.2 N                                                                      H                                                        23W        CH(CH.sub.3).sub.2                                                                      6-CH.sub.3 S                                             23X        CH(CH.sub.3).sub.2                                                                      6-CH.sub.3 SO                                            23Y        CH(CH.sub.3).sub.2                                                                      6-CH.sub.3 SO.sub.2                                      23Z        CH(CH.sub.3).sub.2                                                                      6-F                                                      23AA       CH(CH.sub.3).sub.2                                                                      6-C.sub.6 H.sub.5 S                                      23AB       CH(CH.sub.3).sub.2                                                                      6-(4-CH.sub.3 C.sub.6 H.sub.4 S)                         23AC       CH(CH.sub.3).sub.2                                                                      6-(4-CH.sub.3 OC.sub.6 H.sub.4 S)                        23AD       CH(CH.sub.3).sub.2                                                                      6-(4-ClC.sub.6 H.sub.4 S)                                23AE       CH(CH.sub.3).sub.2                                                                      6-(4-CH.sub.3 -1-naphthyl-S)                             23AF       CH(CH.sub.3).sub.2                                                                      6-(1-naphthyl-S)                                         23AG       CH(CH.sub.3).sub.2                                                                      6-C.sub.6 H.sub.5 SO                                     23AH       CH(CH.sub.3).sub.2                                                                      6-C.sub.6 H.sub.5 SO.sub.2                               23AI       CH(CH.sub.3).sub.2                                                                      6-(4-CH.sub.3 C.sub.6 H.sub.4 SO)                        23AJ       CH(CH.sub.3).sub.2                                                                      6-(4-CH.sub.3 C.sub.6 H.sub.4 SO.sub.2)                  23AK       CH(CH.sub.3).sub.2                                                                      6-(4-CH.sub.3 OC.sub.6 H.sub.4 SO)                       23AL       CH(CH.sub.3).sub.2                                                                      6-(4-CH.sub.3 OC.sub.6 H.sub.4 SO.sub.2)                 23AM       CH(CH.sub.3).sub.2                                                                      6-(4-ClC.sub.6 H.sub.4 SO)                               23AN       CH(CH.sub.3).sub.2                                                                      6-(4-ClC.sub.6 H.sub.4 SO.sub.2)                         23AO       CH(CH.sub.3).sub.2                                                                      6-(4-CH.sub.3 -1-naphthyl-SO)                            23AP       CH(CH.sub.3).sub.2                                                                      6-(4-CH.sub.3 -1-naphthyl-SO.sub.2)                      23AQ       CH(CH.sub.3).sub.2                                                                      6-(1-naphthyl-SO)                                        23AR       CH(CH.sub.3).sub.2                                                                      6-(1-naphthyl-SO.sub.2)                                  23AS       CH(CH.sub.3).sub.2                                                                      6-CH.sub.3 COO                                           23AT       CH(CH.sub.3).sub.2                                                                      6-C.sub.6 H.sub.5 COO                                    23AU       CH(CH.sub.3).sub.2                                                                      6-(1-naphthyl-COO)                                       23AV       CH(CH.sub.3).sub.2                                                                      6-(1-azetidinyl)                                         23AW       CH(CH.sub.3).sub.2                                                                      6-(1-pyrrolidinyl)                                       23AX       CH(CH.sub.3).sub.2                                                                      6-(1-piperidinyl)                                        23AY       CH(CH.sub.3).sub.2                                                                      6-(4-morpholinyl)                                        23AZ       CH(CH.sub.3).sub.2                                                                      6-(4-benzyl-1-piperazinyl)                               23BA       CH(CH.sub.3).sub.2                                                                      6-(4-methyl-1-piperazinyl)                               23BB       CH(CH.sub.3).sub.2                                                                      6-(1-1H-imidazolyl)                                      23BC       CH(CH.sub.3).sub.2                                                                      6-(NHCH.sub.2 COOC.sub.4 H.sub.9 -t)                     23BD       CH(CH.sub.3).sub.2                                                                      6-NH.sub.2                                               23BE       CH(CH.sub.3).sub.2                                                                      6-(1-piperazinyl)                                        23BF       CH(CH.sub.3).sub.2                                                                      6-(NHCH.sub.2 COOH)                                      23BG       CH(CH.sub.3).sub.2                                                                      6-(CH.sub.3 CONH)                                        23BH       CONH.sub.2                                                                              H                                                        23BI       H         CONH.sub.2                                               23BJ       CN        H                                                        ______________________________________                                    

Preparation 23BK

Reaction of isothiazole-5-carboxaldehyde with lithium3-(triphenylphosphoranylidene)propanoate under standard Wittigconditions provides 4-(5-isothiazolyl)-3-butenoic acid which is reducedand cyclized with aluminum chloride to provide4-oxo-4,5,6,7-tetrahydrobenzisothiazole. The 4-oxo compound is reactedwith methylenetriphenyl phosphorane under standard Wittig conditions anda methylene is inserted into the resulting 4-methylene compound via aSimmons Smith reaction to provide 6,7-dihydrospiro [benzisothiazol-4(SH), 1'-cyclopropane]which is oxidized with hydrogen peroxide in aceticacid to give6,7-dihydrospiro[-3-oxo-benzisothiazol-4(5H),1'-cyclopropane 1,1-dioxide(4-spirocyclopropyl tetrahydrosaccharin). This is chloromethylatedaccording to the procedure of Preparation 1A to give2-chloromethyl-4-spirocyclopropyl-4,5,6,7-tetrahydrosaccharin.

Preparation 23BL

2-Benzyl-4-isopropyl-6-oxo-tetrahydrosaccharin of preparation 21 isreduced with sodium borohydride and methylated with methyl iodide in thepresence of sodium hydride to provide2-benzyl-4-isopropyl-6-methoxy-tetrahydrosaccharin. This is debenzylatedand chloromethylated as in preparation 21 to provide2-chloromethyl-4-isopropyl-6-methoxy-4,5,6,7-tetrahydrosaccharin.

Preparation 24

Following a procedure substantially similar to that described by Cale etal. (J. Med. Chem. 1989, 32, 2178) there was prepared:3,5-dichloro-4-pyridinecarboxylic acid, white crystals, m.p. 231°-235°C. (dec.).

Preparation 25

97% sodium hydride (2.72 g. 0.11 mol) was suspended in THF (100 ml)under nitrogen and a solution of N-(2-hydroxyethyl)morpholine (14.4 g,0.11 mol) in THF (15 ml) was added in portions. When hydrogen evolutionhad ceased, a solution of 2,3,5-trichloropyridine (18.2 g, 0.10 mol) inTHF (25 ml) was added at such a rate as to maintain a gentle reflux. Thereaction mixture was refluxed for 2 hours and the solvent wassubsequently removed in vacuo. The residue was taken up in water/CH₂Cl₂, the organic layer was separated and the solvent was removed invacuo to afford 26.3 g (94.9%) of3.5-dichloro-2-[2-(4-morpholinyl]ethoxy]pyridine as a crystalline solid.

A solution of lithium diisopropylamide (6.4 g, 0.06 mol) in THF (100 ml)under nitrogen was cooled to -70° C. and a solution of 3,5-dichloro-2-[2-(4-morpholinyl) ethoxy]pyridine (13.0 g, 0.047 mol) inTHF (10 ml) was added via syringe. The yellow/red solution was stirredfor 30 minutes at -70° C. and then was slowly warmed to roomtemperature. The mixture was poured onto crushed dry ice/THF and uponevaporation of the dry ice the solvent was removed in vacuo. The residuewas taken up in dilute ammonium hydroxide and extracted with chloroform(2X). The organic layer was separated and concentrated in vacuo toafford 6.0 g of recovered starting material. The aqueous layer wasconcentrated in vacuo and 3N HCl was added to the residue. The 15solution was cooled and a solid was obtained which was collected byfiltration. The solid was recrystallized from water to afford3,5-dichloro-2-[2-(4-morpholinyl)ethoxy]pyridine-4-carboxylic acidhydrochloride as a white solid in 71% yield (based on recovered startingmaterial), m.p. 230°-231° C. (dec.).

By a substantially similar process it is contemplated that3,5-dichloro-2-[2-(pyrrolidinyl) ethoxy]pyridine,3,5-dichloro-2-[2-(pyrrolidinyl]ethoxylpyridine-4-carboxylic acidhydrochloride, 3,5-dichloro-2-[2-(piperidinyl]ethoxy]pyridine,3,5-dichloro-2-[2-(piperidinyl)ethoxy]pyridine-4-carboxylic acidhydrochloride, 3,5-dichloro-2-[2-piperazinyl)ethoxy]pyridine,3,5-dichloro-2-[2-(piperazinyl]ethoxy]pyridine-4-carboxylic acidhydrochloride, 3,5-dichloro-2-[2-[4-methylpiperazinyl)ethoxy]-pyridineand 3,5-dichloro-2-[2-(4-methylpiperazinyl]ethoxy]-pyridine-4-carboxylicacid hydrochloride can be prepared from 2,3,5-trichloropyridine and theappropriate N-(2-hydroxyethyl)amine derivative.

Preparation 26

Following a procedure substantially similar to that described inpreparation 25 there was prepared:3.5-dichloro-2-[2-dimethylamino]ethoxy]pyridine, in a 36% yield and3,5-dichloro-2-[2-(dimethylamino]ethoxy]pyridine-4-carboxylic acidhydrochloride in 1.3% yield, m.p. 184°-186° C. (dec.) whenrecrystallized from water.

Preparation 27

Concentrated HCl (450 ml) was added to ethyl 2,4-dioxovalerate ( 177.8g, 1.1 mol ) followed by hydroxylamine hydrochloride (103.7 g, 1.68mol). The reaction mixture was stirred for 7 hours, then allowed tostand for 60 hours. The solvent was removed in vacuo and the residue waschilled on ice. A solid formed which was collected by filtration andwashed with cold water. The solid was dissolved in THF (11), thesolution was filtered and the solvent was removed in vacuo. The residuewas slurried with ethyl acetate (200 ml) and the solid collected byfiltration. Concentration of filtrate to approximately 30 ml afforded asecond crop of the product. The two crops were combined andrecrystallized from methanol to afford 82.1 g (58%) of3-methylisoxazole-5-carboxylic acid, m.p. 209°-211° C.

Preparation Of The Final Products EXAMPLE 1

A mixture of isonicotinic acid (0.98 g, 0.008 mol),2-bromomethylsaccharin (2.11 g, 0.008 mol), triethylamine (0.81 g, 0.008mol) and xylene (25 ml) were refluxed for 1 hour. The solvent wasremoved in vacuo and the residue was partitioned between water andmethylene chloride. The organic layer was separated and the solventremoved in vacuo. The solid residue was recrystallized from CH₃ CN toafford 0.9 g (37%) of 2-saccharinylmethyl pyridine-4-carboxylate as ayellow solid, m.p. 145°-146° C.

EXAMPLE 2

Following a procedure which was substantially similar to that describedin Example 1 but substituting 3,5-dichloro-4-pyridenecarboxylic acid forisonicotinic acid there was obtained 2-saccharinylmethyl3,5-dichloropyridine-4-carboxylate in a 29% yield, m.p. 159°-160° C.

EXAMPLE 3

A solution of the free base of 3,5-dichloro-2-[2-(4-morpholinyl) ethoxy)pyridine-4-carboxylic acid hydrochloride (3.6 g, 0.01 mol) and cesiumcarbonate (4.85 g, 0.015 mol) in methanol (50 ml) was stirred for 30minutes. The methanol was removed in vacuo and the residue was dissolvedin DMF (50 ml). 2-Chloromethyl-4-(isopropyl)saccharin (3.0 g, 0.01 mol)was then added and the reaction mixture was heated at 80° C. for 3hours. The DMF was removed in vacuo, the residue was taken up inmethylene chloride and was filtered through charcoal. The solvent wasremoved in vacuo, the residue was taken up in tert-butyl-methylether andthe solution was filtered. The solvent was removed in vacuo and theresidue was treated with ethereal HCl. A gum was obtained which wastriturated with CH₃ CN to afford 0.5 g (9%) of4-(isopropyl]-2-saccharinylmethyl3.5-dichloro-2-[2-(4-morpholinyl)ethoxy]pyridine-4-carboxylatehydrochloride as a white solid, m.p. 120°-140° C.

EXAMPLE 4

A mixture of 3,5-dichloro-4-pyridinecarboxylic acid (0.42 g, 0.002 mol),cesium carbonate (0.36 g, 0.001 mol) and methanol (10 ml) was stirredfor 30 minutes. The solvent was removed in vacuo and2-chloromethyl-4-isopropylsaccharin (0.55 g, 0.002 mol) and DMF (10 ml)were added to the residue. The mixture was heated to 75° C. and stirredfor 3 hours. The solvent was removed in vacuo and the residue waspartitioned between water/methylene chloride. The organic layer wasseparated, dried over anhydrous MgSO4 and concentrated in vacuo. Theresidue was treated with ethereal HCl to afford a white gum which wastriturated with Et₂ O (2X), then acetone. A white solid was obtainedwhich was collected by filtration and dried in high vacuum to afford0.14 g (15%) of 4-isopropyl-2-saccharinylmethyl3,5-dichloro-pyridine-4-carboxylate hydrochloride, m.p. 93°-95° C.

EXAMPLE 5

A mixture of3,5-dichloro-2-[2-(dimethylamino)ethoxy)-pyridine-4-carboxylic acidhydrochloride (2.65 g, 0.0084 mol), cesium carbonate (4.1 g, 0.013 mol),tetrabutylammonium bromide (1.0 g, 0.003 mol) and DMF (25 ml) wasstirred for 10 minutes, then2-chloromethyl-4-isopropyl-6-methoxysaccharin (2.4 g, 0.0084 mol) wasadded. The mixture was heated to 80° C. and stirred for 1 hour. Thesolvent was removed in vacuo and the residue was partitioned betweenwater/methylene chloride. The organic layer was separated, washed withwater, dried over anhydrous MgSO4 and concentrated in vacuo. The residuewas dissolved in ethyl acetate and filtered through a plug of silica.Ethereal HCl was added to the filtrate and the solvent was removed invacuo. The residue was washed with ether (50 ml), treated with saturatedNaHCO₃ and extracted with methylene chloride. The solvent was removed invacuo, the residue was triturated with methanol and an off-white solidwas collected by filtration. The product was dried in high vacuum toafford 0.096 g (2.1%) of 4-isopropyl-6-methoxy-2-saccharinylmethyl3,5-dichloro-2-[2-(dimethylamino)ethoxy]pyridine-4-carboxylate, m.p.155°-160° C. (dec).

By a substantially similar process it is contemplated that4-isopropyl-6-methoxy-2-saccharinylmethyl3,5-dichloro-2-[2-(pyrrolidinyl)ethoxy]pyridine-4-carboxylate,4-isopropyl-6-methoxy-2-saccharinylmethyl3,5-dichloro-2-[2-(piperidinyl)-ethoxy]pyridine-4-carboxylate,4-isopropyl-6-methoxy-2-saccharinylmethyl3,5-dichloro-2-[2-(piperazinyl)ethoxy]pyridine-4-carboxylate,4-isopropyl-6-methoxy-2-saccharinylmethyl3,5-dichloro-2-[2-(4-methylpiperazinyl)ethoxy]pyridine-4-carboxylate,4-isopropyl-6-methoxy-2-saccharinylmethyl2-trifluoromethyl-pyridine-4-carboxylate and4-isopropyl-6-methoxy-2-saccharinylmethyl2-methoxypyridine-4-carboxylate can be prepared from2-chloromethyl-4-isopropyl-6-methoxysaccharin and the appropriatecarboxylic acid derivative.

EXAMPLE 6

A mixture of 3-thiophene carboxylic acid (0.26 g, 2.0 mmol), K₂ CO₃(0.28 g, 2.0 mmol) and DMF (4 ml) was stirred for 1 hour.2-Chloromethyl-4-isopropyl-6-methoxy-saccharin (0.61 g, 2.0 mmol) wasthen added and the mixture was stirred for 24 hours. Water (20 ml) wasadded to the reaction mixture and the solution was extracted with ether(2×40 ml). The organic layer was separated, washed with water, thenbrine and was dried over anhydrous Na₂ SO₄. The solvent was removed invacuo and the solid residue was recrystallized from toluene/hexane toafford 0.5 g (65%) of 4-isopropyl-6-methoxy-2-saccharinylmethylthiophene-3-carboxylate as a white powder, m.p. 125°-127° C.

By a substantially similar process it is contemplated that4-isopropyl-6-methoxy-2-saccharinylmethyl-4-methoxythiophene-3-carboxylatecan be prepared from 2-chloromethyl-4-isopropyl-6-methoxysaccharin and4-methoxy-3-thiophene carboxylic acid.

EXAMPLE 7

Following a procedure substantially similar to that described in Example6 but substituting 3-methyl-2-thiophene carboxylic acid for 3-thiophenecarboxylic acid there was obtained4-isopropyl-6-methoxy-2-saccharinylmethyl3-methylthiophene-2-carboxylate as a white powder in 78% yield, m.p.132°-134° C.

EXAMPLE 8

Following a procedure substantially similar to that described in Example6 but substituting 2-thiophene carboxylic acid for 3-thiophenecarboxylic acid there was obtained4-isopropyl-6-methoxy-2-saccharinylmethyl thiophene-2-carboxylate aswhite crystals in 62% yield, m.p. 139°-141° C.

EXAMPLE 9

Following a procedure substantially similar to that described in Example6 but substituting 3-chloro-2-thiophene carboxylic acid for 3-thiophenecarboxylic acid there was obtained4-isopropyl-6-methoxy-2-saccharinylmethyl3-chlorothiophene-2-carboxylate as an off-white powder in 65% yield,m.p. 138°-140° C.

EXAMPLE 10

A mixture of 3-methylisoxazole-5-carboxylic acid (0.63 g, 5.0 mmol),cesium carbonate (0.8 g, 2.45 mmol) and methanol was stirred for 30minutes. The solvent was removed in vacuo and the residue was dried inhigh vacuum for 1 hour. The residue was suspended in DMF (30 ml) and2-chloromethyl-4-isopropyl-6-methoxysaccharin (1.0 g, 3.3 mmol) wasadded. The mixture was stirred at room temperature for 19 hours and waspoured into water. The mixture was extracted with ethyl acetate/ether(4/1, 300 ml) and the organic layer was separated and wash with water,then brine. The solvent was removed in vacuo and the residue waspurified by flash chromatography (30% ethyl acetate/hexanes) to afford1.1 g (85%) of 4-isopropyl-6-methoxy-2-saccharinylmethyl3-methylisoxazole-5-carboxylate as a white powder, m.p. 157°-158° C.

A mixture of 2-pyrrolidone-5-carboxylic acid (0.85 g, 6.6 mmol), cesiumcarbonate (1.07 g, 3.3 mmol) and methanol was stirred for 30 minutes.The solvent was removed in vacuo and the residue was dried in highvacuum for 1 hour. The residue was suspended in DMF (30 ml) and2-chloromethyl-4-isopropyl-6-methoxysaccharin (1.0 g, 3.3 mmol) wasadded. The mixture was stirred at room temperature for 24 hours and waspoured into water. The mixture was extracted with ethyl acetate/ether(4/1) and the organic layer was separated and washed with water, thenbrine. The solvent was removed in vacuo and the residue was purified byflash chromatography (CH₂ Cl₂ followed by 2% methanol/CH₂ Cl₂) to afford0.56 g (53%) of4-isopropyl-6-methoxy-2-saccharinylmethyl-2-pyrrolidine-5-carboxylate,m.p. 159°-160° C.

EXAMPLE 12

Acetonitrile (3 ml), followed by N,N-diisopropylethylamine (0.26 ml, 1.5mmol) were added to 3,5-dimethylisoxazole-4-carboxylic acid (0.21 g, 1.5mmol). The mixture was stirred for 5 minutes, then2-chloromethyl-4-isopropyl-6-methoxysaccharin (0.30 g, 1 mmol) wasadded. The reaction mixture was stirred at room temperature for 18hours, diluted with ethyl acetate (75 ml) and washed with saturatedNaHCO₃. The organic layer was dried over anhydrous Na₂ SO₄, filtered andconcentrated in vacuo. The residue was purified by preparative layerchromatography eluting with CH₂ Cl₂ (100%) to afford 0.041 g (10%) of4-isopropyl-6-methoxy-2-saccharinylmethyl3,5-dimethylisoxazole-4-carboxylate as a white solid, m.p. 136.8°-139.1°C.

EXAMPLE 13

Acetonitrile (3 ml), followed by N,N-diisopropylethylamine (0.26 ml, 1.5mmol) were added to 3,5-dimethyl-1-phenylpyrazole-4-carboxylic acid(0.44 g, 2.0 mmol). The mixture was stirred for 5 minutes then2-chloromethyl-4-isopropyl-6-methoxysaccharin (0.30 g, 1 mmol) wasadded. The reaction mixture was stirred at room temperature for 35hours, then at 80° C. for 1 hour. The mixture was diluted with ethylacetate (75 ml), washed with saturated NaHCO₃, and the organic layer wasdried over Na₂ SO₄. The solvent was removed in vacuo and the residue wasrecrystallized from ethanol to afford 0.31 g (64%) of4-isopropyl.-6-methoxy-2-saccharinylmethyl3,5-dimethyl-1-phenylpyrazole-4-carboxylate as a yellow solid, m.p.167.3°-169.4° C.

EXAMPLE 14

Acetonitrile (20 ml), followed by N,N-diisopropylethylamine (5.8 ml, 33mmol) were added to 2,4-dimethyl-3-pyridinecarboxylic acid (5.1 g, 33mmol). The mixture was stirred for 5 minutes, then2-chloromethyl-4-isopropyl-6-methoxysaccharin (4.3 g, 14 mmol) wasadded. The reaction mixture was stirred at room temperature for 47hours, then at 80° C. for 1 hour. The mixture was diluted with ethylacetate (100 ml), washed with saturated NaHCO₃, and the organic layerwas dried over Na₂ SO₄. The solvent was removed in vacuo and the residuewas recrystallized from ether to afford 3,4 g (57%) of4-isopropyl-6-methoxy-2-saccharinylmethyl 2,4-dimethylpyridine-3carboxylate, m.p. 132.1°-133.5° C.

EXAMPLE 15

Following a procedure substantially similar to that described in Example11 but substituting 1,3-dimethyl-5-chloroindole 2-carboxylic acid(prepared via a standard Fischer indole synthesis using4-chlorophenylhydrazine hydrochloride and α-ketobutyric acid, followedby N-methylation of the resulting ethyl3-methyl-5-chloroindole-2-carboxylate and saponification of the ester)for 2-pyrrolidone-5-carboxylic acid there was obtained4-isopropyl-6-methoxy-2-saccharinylmethyl1,3-dimethyl-5-chloro-indole-2-carboxylate as white crystals in 38%yield, m.p. 183°-184° C. when recrystallized from ethyl acetate/hexanes.

EXAMPLE 16

Following a procedure substantially similar to that described in Example11 but substituting furan-3-carboxylic acid, pyrrole-2-carboxylic acid,1-methylpyrrole-2-carboxylic acid, pyrazole-4-carboxylic acid,pyrrolidine-2-carboxylic acid, isoxazole-5-carboxylic acid, orimidazole-2-carboxylic acid for 2-pyrrolidone-5-carboxylic acid it iscontemplated that the following can be prepared:4-isopropyl-6-methoxy-2-saccharinylmethyl furan-3-carboxylate4-isopropyl-6-methoxy-2-saccharinylmethyl pyrrole-2-carboxylate,4-isopropyl-6-methoxy-2-saccharinylmethyl pyrrole-2-carboxylate,4-isopropyl-6-methoxy-2-saccharinylmethyl pyrazole-4-carboxylate,4-isopropyl-6-methoxy-2-saccharinylmethyl pyrrolidine-2-carboxylate,4-isopropyl-6-methoxy-2-saccharinylmethyl isoxazole-5-carboxylate and4-isopropyl-6-methoxy-2-saccharinylmethyl imidazole-2-carboxylate.

EXAMPLE 17

By reaction of an appropriate 4-R⁴ -R⁵ -2-halo-methylsaccharin offormula IV with an appropriate heterocyclylcarboxylic acid usingprocedures substantially similar to those described above in Examples 1,3 and 5, it is contemplated that the compounds of formula I listed inTABLE 1 can be prepared.

                                      TABLE 1                                     __________________________________________________________________________    Example                                                                             R.sup.4 R.sup.5       Het                                               __________________________________________________________________________    17A   Br      H             4-pyridyl                                         17B   Cl      H             3-thienyl                                         17C   CH.sub.3 O                                                                            H             3,5-Cl.sub.2 -4-pyridyl                           17D   CH(C.sub.2 H.sub.5).sub.2                                                             H             3,5-Cl.sub.2 -4-pyridyl                           17E   CH.sub.3 O                                                                            6-CH.sub.3 O  3,5-Cl.sub.2 -4-pyridyl                           17F   H       7-Cl          3,5-Cl.sub.2 -4-pyridyl                           17G   CH.sub.3 O                                                                            5-CH.sub.3 O  3-CH.sub.3 -5-isoxazolyl                          17H   COOCH.sub.3                                                                           H             3,5-Cl.sub.2 -4-pyridyl                           17I   C.sub.2 H.sub.5 O                                                                     H             3-quinolinyl                                      17J   (CH.sub.3).sub.2 CHO                                                                  H             3,5-Cl.sub.2 -4-pyridyl                           17L   H       6-NO.sub.2    3,5-Cl.sub.2 -4-pyridyl                           17M   H       5-(CH.sub.3).sub.3 CCH.sub.2 C(CH.sub.3).sub.2                                              3,5-Cl.sub.2 -4-pyridyl                           17N   H       4,7-(CH.sub.3 O).sub.2                                                                      3,5-Cl.sub.2 -4-pyridyl                           17-O  C.sub.2 H.sub.5 O                                                                     7-CH.sub.3 (OCH.sub.2 CH.sub.2).sub.2 O                                                     3-quinolinyl                                      17P   CH.sub.3 O                                                                            7-CH.sub.3 (OCH.sub.2 CH.sub.2).sub.2 O                                                     3,5-Cl.sub.2 -4-pyridyl                           17Q   n-C.sub.3 H.sub.7                                                                     H             3,5-Cl.sub.2 -4-pyridyl                           17R   CH.sub.3                                                                              7-CH.sub.3    2-oxo-5-pyrrolidinyl                              17T   CF.sub.3                                                                              H             3,5-(CH.sub.3).sub.2 -4-isoxazolyl                17U   CCl.sub.3                                                                             H             3,5-Cl.sub.2 -4-pyridyl                           17V   H       6-cyclohexyl  3,5-Cl.sub.2 -4-pyridyl                           17W   H       6-CH.sub.3 SO.sub.2 NH                                                                      3,5-Cl.sub.2 -4-pyridyl                           17X   H       6-CF.sub.3 SO.sub.2 NH                                                                      3-isoquinolinyl                                   17Y   H       6-CCl.sub.3 SO.sub.2 NH                                                                     3,5-Cl.sub.2 -4-pyridyl                           17Z   H       6-CN          3,5-Cl.sub.2 -4-pyridyl                           17AA  H       6-NH.sub.2 SO.sub.2                                                                         3,5-Cl.sub.2 -4-pyridyl                           17AB  H       6-CH.sub.3 SO.sub.2 NHSO.sub.2                                                              3,5-Cl.sub.2 -4-pyridyl                           17AC  H       6-CH.sub.3 SO.sub.2                                                                         3-isoquinolinyl                                   17AD  H       6-CF.sub.3 SO.sub.2                                                                         3,5-Cl.sub.2 -4-pyridyl                           17AE  H       6-HOOC        3,5-Cl.sub.2 -4-pyridyl                           17AF  H       6-HOCH.sub.2  3,5-Cl.sub.2 -4-pyridyl                           17AG  H       6-OHC         3,5-Cl.sub.2 -4-pyridyl                           17AH  H       6-NH.sub.2 CH.sub.2                                                                         3,5-Cl.sub.2 -4-pyridyl                           17AI  H       6-CF.sub.3    3,5-(CH.sub.3).sub.2 -1-C.sub.6 H.sub.5 -                                     4-pyrazolyl                                       17AJ  H       6-CCl.sub.3   3,5-Cl.sub.2 -4-pyridyl                           17AK  CH═CH.sub.2                                                                       H             3,5-Cl.sub.2 -4-pyridyl                           17AL  C.tbd.CH                                                                              H             3,5-Cl.sub.2 -4-pyridyl                           17AM  NH.sub.2                                                                              H             3,5-Cl.sub.2 -4-pyridyl                           17AN  CH.sub.3 NH                                                                           H             1,3-(CH.sub.3).sub.2 -5-Cl-                                                   2-indolyl                                         17AO  (CH.sub.3).sub.2 N                                                                    H             3,5-Cl.sub.2 -4-pyridyl                           17AP  CH(CH.sub.3).sub.2                                                                    6-CH.sub.3 S  3,5-Cl.sub.2 -4-pyridyl                           17AQ  CH(CH.sub.3).sub.2                                                                    6-CH.sub.3 SO 3,5-Cl.sub.2 -4-pyridyl                           17AR  CH(CH.sub.3).sub.2                                                                    6-CH.sub.3 SO.sub.2                                                                         3,5-Cl.sub.2 -4-pyridyl                           17AS  CH(CH.sub.3).sub.2                                                                    6-F           3-CH.sub.3 -2-thienyl                             17AT  CH(CH.sub.3).sub.2                                                                    6-C.sub.6 H.sub.5 S                                                                         3,5-Cl.sub.2 -4-pyridyl                           17AU  CH(CH.sub.3).sub.2                                                                    6-(4-CH.sub.3 C.sub.6 H.sub.4 S)                                                            3,5-Cl.sub.2 -4-pyridyl                           17AV  CH(CH.sub.3).sub.2                                                                    6-(4-CH.sub.3 OC.sub.6 H.sub.4 S)                                                           3,5-Cl.sub.2 -4-pyridyl                           17AW  CH(CH.sub.3).sub.2                                                                    6-(4-ClC.sub.6 H.sub.4 S)                                                                   3,5-Cl.sub.2 -4-pyridyl                           17AX  CH(CH.sub.3).sub.2                                                                    6-(4-CH.sub.3 -1-naphthyl-S)                                                                5-benzimidazolyl                                  17AY  CH(CH.sub.3).sub.2                                                                    6-(1-naphthyl-S)                                                                            3,5-Cl.sub.2 -4-pyridyl                           17AZ  CH(CH.sub.3).sub.2                                                                    6-C.sub.6 H.sub.5 SO                                                                        3,5-Cl.sub.2 -4-pyridyl                           17BA  CH(CH.sub.3).sub.2                                                                    6-C.sub.6 H.sub.5 SO.sub.2                                                                  3,5-Cl.sub.2 -4-pyridyl                           17BB  CH(CH.sub.3).sub.2                                                                    6-(4-CH.sub.3 C.sub.6 H.sub.4 SO)                                                           3,5-Cl.sub.2 -4-pyridyl                           17BC  CH(CH.sub.3).sub.2                                                                    6-(4-CH.sub.3 C.sub.6 H.sub.4 SO.sub.2)                                                     2-benzofuranyl                                    17BD  CH(CH.sub.3).sub.2                                                                    6-(4-CH.sub.3 OC.sub.6 H.sub.4 SO)                                                          3,5-Cl.sub.2 -4-pyridyl                           17BE  CH(CH.sub.3).sub.2                                                                    6-(4-CH.sub.3 OC.sub.6 H.sub.4 SO.sub.2)                                                    3,5-Cl.sub.2 -4-pyridyl                           17BF  CH(CH.sub.3).sub.2                                                                    6-(4-ClC.sub.6 H.sub.4 SO)                                                                  3,5-Cl.sub.2 -4-pyridyl                           17BG  CH(CH.sub.3).sub.2                                                                    6-(4-ClC.sub.6 H.sub.4 SO.sub.2)                                                            2-quinoxalinyl                                    17BH  CH(CH.sub.3).sub.2                                                                    6-(4-CH.sub.3 -1-naphthyl-SO)                                                               3,5-Cl.sub.2 -4-pyridyl                           17BI  CH(CH.sub.3).sub.2                                                                    6-(4-CH.sub.3 -1-naphthyl-SO.sub.2)                                                         3,5-Cl.sub.2 -4-pyridyl                           17BJ  CH(CH.sub.3).sub.2                                                                    6-(1-naphthyl-SO)                                                                           3,5-Cl.sub.2 -4-pyridyl                           17BK  CH(CH.sub.3).sub.2                                                                    6-(1-naphthyl-SO.sub.2)                                                                     3,5-Cl.sub.2 -4-pyridyl                           17BL  CH(CH.sub.3).sub.2                                                                    6-CH.sub.3 COO                                                                              3,5-Cl.sub.2 -4-pyridyl                           17BM  CH(CH.sub.3).sub.2                                                                    6-C.sub.6 H.sub.5 COO                                                                       2-quinoxalinyl                                    17BN  CH(CH.sub.3).sub.2                                                                    6-(1-naphthyl-COO)                                                                          3,5-Cl.sub.2 -4-pyridyl                           17BO  CH(CH.sub.3).sub.2                                                                    6-(1-azetidinyl)                                                                            3,5-Cl.sub.2 -4-pyridyl                           17BP  CH(CH.sub.3).sub.2                                                                    6-(1-pyrrolidinyl)                                                                          3,5-Cl.sub.2 -4-pyridyl                           17BQ  CH(CH.sub.3).sub.2                                                                    6-(1-piperidinyl)                                                                           3,5-Cl.sub.2 -4-pyridyl                           17BR  CH(CH.sub.3).sub.2                                                                    6-(4-morpholinyl)                                                                           2-thianapthenyl                                   17BS  CH(CH.sub.3).sub.2                                                                    6-(4-benzyl-1-piperazinyl)                                                                  3,5-Cl.sub.2 -4-pyridyl                           17BT  CH(CH.sub.3).sub.2                                                                    6-(4-methyl-1-piperazinyl)                                                                  3,5-Cl.sub.2 -4-pyridyl                           17BU  CH(CH.sub.3).sub.2                                                                    6-(1-1H-imidazolyl)                                                                         3,5-Cl.sub.2 -4-pyridyl                           17BV  CH(CH.sub.3).sub.2                                                                    6-(NHCH.sub.2 COOC.sub.4 H.sub.9 -t)                                                        3,5-Cl.sub.2 -4-pyridyl                           17BW  CH(CH.sub.3).sub.2                                                                    6-NH.sub.2    2-benzothiazolyl                                  17BX  CH(CH.sub.3).sub.2                                                                    6-(1-piperazinyl)                                                                           3,5-Cl.sub.2 -4-pyridyl                           17BY  CH(CH.sub.3).sub.2                                                                    6-(NHCH.sub.2 COOH)                                                                         3,5-Cl.sub.2 -4-pyridyl                           17BZ  CH(CH.sub.3).sub.2                                                                    6-(CH.sub.3 CONH)                                                                           3,5-Cl.sub.2 -4-pyridyl                           17CA  CONH.sub.2                                                                            H             3,5-Cl.sub.2 -4-pyridyl                           17CB  CH.sub.3                                                                              H             2-benzisothiazolyl                                17CC  Ph      H             3,5-Cl.sub.2 -4-pyridyl                           17CD  (CH.sub.3).sub.3 C                                                                    H             3,5-Cl.sub.2 -4-pyridyl                           17CE  C.sub.2 H.sub.5 CHCH.sub.3                                                            H             3,5-Cl.sub.2 -4-pyridyl                           17CF  n-C.sub.3 H.sub.7                                                                     5,6-(CH.sub.3 O).sub.2                                                                      5-benzimidazolyl                                  17CG  CH(CH.sub.3).sub.2                                                                    5,6-(CH.sub.3 O).sub.2                                                                      3,5-Cl.sub.2 -4-pyridyl                           17CH  CH.sub.3 O                                                                            5-CH.sub.3 O  3,5-Cl.sub.2 -4-pyridyl                           17CI  C.sub.2 H.sub.5                                                                       5,7-(CH.sub.3 O).sub.2                                                                      3,5-Cl.sub.2 -4-pyridyl                           17CJ  CH.sub.3                                                                              H             3,5-Cl.sub.2 -4-pyridyl                           17CK  CH.sub.3 O                                                                            7-CH.sub.3 O  3-(1,8-naphthyridinyl)                            17CL  C.sub.2 H.sub.5                                                                       H             3,5-Cl.sub.2 -4-pyridyl                           17CM  CH(CH.sub.3).sub.2                                                                    6-OH          3,5-Cl.sub.2 -4-pyridyl                           17CN  CH(CH.sub.3).sub.2                                                                    6-N(CH.sub.3).sub.2 -7-Cl                                                                   3,5-Cl.sub.2 -4-pyridyl                           17CO  CH(CH.sub.3).sub.2                                                                    6,7-CH.sub.3 O                                                                              3,5-Cl.sub.2 -4-pyridyl                           17CP  CH(CH.sub.3).sub.2                                                                    6,7-methylenedioxy                                                                          3,5-Cl.sub.2 -4-pyridyl                           17CQ  OH      H             3,5-Cl.sub.2 -4-pyridyl                           __________________________________________________________________________

EXAMPLE 17CO

It is contemplated that following the procedure of Example 17,2-chloromethyl-4-spirocyclopropyl-4,5,6,7-tetrahydrosaccharin ofpreparation 23BI can be coupled with 2,4-dimethyl-3-pyridinecarboxylicacid to provide4-spirocyclopropyl-4,5,6,7-tetrahydro-2-saccharinylmethyl2,4-dimethylpyridine-3-carboxylate.

EXAMPLE 17CR

It is contemplated that following the procedure of Example 17,2-chloromethyl-4-isopropyl-6-methoxy-4,5,6,7-tetrahydrosaccharin ofpreparation 23BJ can be coupled with 2,4-dimethyl-3-pyridinecarboxylicacid to provide4-isopropyl-6-methoxy-4,5,6,7-tetrahydro-2-saccharinylmethyl2,4-dimethylpyridine-3-carboxylate.

EXAMPLE 18A

It is contemplated that 6-ethoxy-4-isopropyl-2-saccharinylmethyl3,5-dichloropyridine-4-carboxylate can be prepared by treatment of6-hydroxy-4-isopropyl-2-saccharinylmethyl3,5-dichloropyridine-4-carboxylate with triphenylphosphine and diethylazodicarboxylate in the presence of ethanol.

Following a procedure substantially similar to that of Example 18A it iscontemplated that the compounds of Table 2 can be prepared from6-hydroxy-4-isopropyl-2-saccharinylmethyl3,5-dichloropyridine-4-carboxylate and the appropriate alcohol.

                  TABLE 2                                                         ______________________________________                                        Example       R.sup.5                                                         ______________________________________                                        18B           6-OCH(CH.sub.3).sub.2                                           18C                                                                                          ##STR13##                                                      18D           6-(OCH.sub.2 CH.sub.2).sub.2 OCH.sub.3                          18E           6-OCH.sub.2 COOCH.sub.3                                         18F           6-OCH.sub.2 CH(OCH.sub.3)CH.sub.2 OCH.sub.3                     18G           6-O-cyclobutyl                                                  18H           6-OPO(OC.sub.2 H.sub.5).sub.2                                   18I                                                                                          ##STR14##                                                      18J                                                                                          ##STR15##                                                      18K                                                                                          ##STR16##                                                      18L           6-O(CH.sub.2).sub.2 N(CH.sub.3).sub.2                           18M                                                                                          ##STR17##                                                      18N                                                                                          ##STR18##                                                      ______________________________________                                    

The glycerol which can be used in the synthesis of Example 18F wasobtained as follows:

A solution of 10.0 g (0.055 mol) of DL-α-O-benzylglycerol in a littleTHF was added to a suspension of 15.38 g (0.137 mol) of potassiumtert-butoxide in 300 mL of THF. The mixture was stirred for 1 hr at RTand 18.72 (0.132 mol) of iodomethane was added. A white solidimmediately separated. The reaction was stirred for 10 hr at RT, cooled,carefully diluted with sodium chloride solution and extracted withether. The organic layer was washed with water, 5% HCl, water andsaturated NaCl and dried. The solvent was removed and the residue waspurified by flash chromatography to give1-benzyloxy-2,3-dimethoxypropane, 9.16 g (79%), as an oil.

A solution of 8.8 g (0.042 mol) of this material in 200 ml of MeOH washydrogenated using 1.1 g of 10% Pd/C at 50 psi. The catalyst was removedby filtration and the solvent under reduced pressure to give 4.4 g (87%)of 2,3-dimethoxy-1-propanol.

EXAMPLE 18O

6-Ethoxy-4-isopropyl-2-phenylthiomethylsaccharin was prepared from the6-hydroxy analog (Preparation 19) by the procedure of Example 18A in 85%yield as a solid, mp 111.5°-112.5° C. which was converted to2-chloromethyl-6-ethoxy-4-isopropylsaccharin in 91% yield, mp 127°-128°C. following the procedure of Preparation 18A.

EXAMPLE 18P

Following a procedure substantially similar to that described in Example18A it is contemplated that 4-benzyloxy-2-saccharinylmethyl3,5-dichloropyridine-4-carboxylate can be prepared from benzyl alcoholand 4-hydroxy-2-saccharinylmethyl 3,5-dichloropyridine-4-carboxylate.

EXAMPLE 19

It is contemplated that 6-hydroxy-4-isopropyl-2-saccharinylmethyl3,5-dichloropyridine-4-carboxylate can be treated withtrifluoromethanesulfonic anhydride in the presence of triethylamine toafford 4-isopropyl-6-trifluoromethanesulfonyloxysaccharinylmethyl3,5-dichloropyridine-4-carboxylate.

The trifluoromethanesulfonate can then be heated with1-methyl-2-trimethylstannyl-pyrrole, tetrakis (triphenylphosphine)palladium (0), lithium chloride and 2,6-di-tert-butyl-4-methylphenol andp-dioxane to produce4-isopropyl-6-[2-[1-methyl]pyrrolyl]saccharinylmethyl3,5-dichloropyridine-4-carboxylate.

EXAMPLE 20

It is contemplated that treatment of the trifluoromethanesulfonate ofExample 19 with dimethylamine will produce4-isopropyl-6-dimethylaminosaccharinylmethyl3,5-dichloropyridine-4carboxylate.

EXAMPLE 21

It is contemplated that heating a mixture of4-isopropyl-6-hydroxy-2-saccharinylmethyl3,5-dichloropyridine-4-carboxylate and di-(sec-butoxymethyl)methylaminein toluene will produce2-(3,5-dichloro-4-pyridylcarboxymethyl)-4-isopropyl-8-methyl-2,3,7,8-tetrahydro-9H-[1,3]oxazino[6,5-g]benzisothiazol-3-one1.1-dioxide.

EXAMPLE 22

It is contemplated that treatment of the isopropylidene of Example 18C,Table 2, with p-toluenesulfonic acid monohydrate in methanol-chloroformwill afford 6-(2,3-dihydroxypropoxy]-4-isopropylsaccharinylmethyl3,5-dichloropyridine-4-carboxylate.

EXAMPLE 23

It is contemplated that treatment of6-hydroxy-4-isopropyl-2-saccharinylmethyl3,5-dichloropyridine-4-carboxylate with t-butyl bromoacetate and K₂ CO₃in acetone will afford6-(2-t-butoxy-2-oxoetholy)-4-isopropyl-2-saccharinylinethyl3,5-dichloropyridine-4-carboxylate.

In a similar manner6-(2-benzyloxy-2-oxoethoxy]-4-isopropyl-2-saccharinylmethyl3,5-dichloropyridine-4-carboxylate can be prepared using benzylbromoacetate.

EXAMPLE 24A

To freshly distilled cyclopentadiene (25 mL) at 0° C. was added4-bromo-2-(tert-butyl)isothiaziol-3 (2H)-one 1,1-dioxide (Helv. Chim.Acta., 72, 1416, 1989) (7.9 g, 0.03 mol). After stirring at 0° C. undernitrogen for 16 hr, the reaction mixture was concentrated in vacuo. Theresidue was purified by filtering through silica gel, eluting withhexanes (500 mL) followed by 20% ethyl acetate in hexanes (500 mL). Thelatter eluents were concentrated in vacuo to give 9.8 g (100% of thenorbornene adduct,3a-bromo-2-t-butyl-3a,4,7,7a-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H)-one,1,1-dioxide, as a white solid.

The adduct (0.4 g, 1.2 mmol) in 25 mL of ethyl acetate containing 5% Pdon CaCO₃ (0.2 g) was stirred under one atmosphere of hydrogen for 4 hr,and the reaction mixture was filtered through a pad of silica gel,eluting with ethyl acetate (100 mL). The eluents were concentrated invacuo and the residue crystallized from hexanes to give 0.4 g (100%) ofthe bromo norbornane as a white crystalline solid.

To a solution of the bromo norbornane (3.7 g, 0.011 mol) in toluene (25mL) at 0° C. was added diazabicyclo-nonene (1.37 g, 0.011 mol) intoluene (10 mL). After stirring at 0° C. for 20 min, silica gel (25 g)was added to the reaction mixture. The resulting slurry was loaded ontop of a 15 cm pad of silica gel and eluted with 20% ethyl acetate inhexanes (800 mL). The eluents were concentrated in vacuo to give 2.8 g(100%) of the dehydrobrominated compound as a white solid.

The 2-t-butyl-4,5,6,7-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H)one1,1-dioxide (2.8 g, 0.011 mol) in trifluoroacetic acid (30 mL) washeated at reflux for 48 hr and let stand at room temperature for 4 days.The resulting mixture was concentrated in vacuo, treated with methanol(20 mL) and evaporated to dryness. The residue was taken up in ether(100 mL) and washed with saturated NaHCO₃ (1×50 mL). The layers wereseparated, the aqueous phase acidified to pH 1 with 2N HCl and extractedwith MDC (2×100 mL). The combined organic extracts were dried andconcentrated in vacuo to give 0.9 g (42%) of the bicyclo (2.2.1)saccharin derivative as a white solid.

A mixture of the bicyclo (2,2,1) saccharin derivative, (0.9 g, 5 mmol),chloromethyl phenylsulfide (0.07 g, 7 mmol) and tetrabutylammoniumbromide (0.36 g, 0.16 mmol) in toluene (50 mL) was refluxed undernitrogen for 16 hr, cooled to room temperature and evaporated to drynessunder vacuum. The residue was purified by flash chromatography on silicagel (100 g) using 100% MDC as the eluent to give 1.05 (72%) of thesulfide as a viscous oil.

The sulfide (1.05 g, 3 mmol) in dichloromethane (100 mL) was treatedwith sulfuryl chloride (0.66 g, 5 mmol) and stirred for 2 hr. Theresulting yellow solution was diluted with MDC (100 mL), washed withsaturated NaHCO3 solution, dried and concentrated in vacuo. The residuewas purified by flash chromatography on silica gel (33% MDC in hexanes)to give 0.66 g (81%) of2-chloromethyl-4,5,6,7-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H)-one1,1-dioxide.

It is contemplated that treatment of the 2-chloromethyl compound with3,5-dichloro-4-pyridine carboxylic acid, 3-methyl-2-thiophene carboxylicacid, furan-3-carboxylic acid, 2-trifluoromethyl-4-pyridine carboxylicacid, 2-methoxy-4-pyridine carboxylic acid or3,5-dichloro-2-[2-(4-morpholinyl) ethoxy]-pyridine-4-carboxylic acid,respectively, using procedures similar to those described in Example 17will produce2-(3,5-dichloro-4-pyridylcarbonyloxymethyl)-4,5,6,7-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H)-one1,1-dioxide,2-(3-methyl-2-thienylcarbonyloxymethyl)-4,5,6,7-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H)-one1,1-dioxide:2-(3-furanylcarbonyloxymethyl]-4,5,7-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H)-one1,1-dioxide,2-(2-trifluoromethyl-4-pyridylcarbonyloxymethyl]-4,5,6,7-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H)-one1,1-dioxide,2-(2-methoxy-4-pyridylcarbonyloxymethyl]-4.5,6,7-tetrahydro-4,7-methanol-1,2-benzisothiazol-3(2H)-one1,1-dioxide or2-(3,5-dichloro-2-[2-{4-morpholinyl)ethoxy]-4-pyridylcarbonyloxymethyl)-4,5,6,7-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H)-one1,1-dioxide.

EXAMPLE 24B AND 24C

By a process analagous to that of Example. 24A, it is contemplated thatcyclohexadiene and 1,1-dimethylcyclopentadiene may be convertedrespectively to2-chloromethyl-4,5,6,7-tetrahydro-4,7-ethano-1,2benzisothiazol-3(2H)-one1,1-dioxide and2-chloromethyl-8,8-dimethyl-4,5,6,7-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H)-one1,1-dioxide, which in turn can be treated with an appropriateheterocyclic carboxylic acid using procedures similar to those describedin Example 17 to afford2-(3-methylisoxazolylcarboxymethyl)-4,5,6,7-tetrahydro-4,7-ethano-1,2-benzisothiazol-3(2H)-one1,1-dioxide,2-(1,3-dimethyl-5-chloro-2-indolycarbonyloxymethyl)-4,5,6,7-tetrahydro-4,7-ethano-1,2-benzisothiazol-3(2H)-one1,1-dioxide,2-(2-imidazolylcarbonyloxymethyl)-4,5,6,7-tetrahydro-4,7-ethano-1,2-benzisothiazol-3(2H)-one1,1-dioxide,2-(2-oxo-5-pyrrolidinylcarbonyloxymethyl)-8,8-dimethyl-4,5,6,7-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H)-one1,1,-dioxide,2-(3,5-dimethyl-1-phenyl-4-pyrazolylcarbonyloxymethyl)-8,8-dimethyl-4,5,6,7-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H]-one1,1-dioxide: or2-(1-methyl-2-pyrrolylcarbonyloxymethyl)-8,8-dimethyl-4,5,6,7-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H)-one1,1-dioxide.

EXAMPLES 25A-25

General procedure for the preparation of methyl-2-alkyl-cyclohexan-6-onecarboxylate: To a suspension of anhydrous CuI (10 mmol) in anhydrous THF(100 mL) was added Me₂ S (100 mmol) and the resulting solution wascooled to -78°C. The appropriate alkyl lithium reagent (20 mmol) wasadded over a period of 15 min. After being stirred at -78° C. for anhour, a solution of cyclohexenone (10 mmol) in THF was added andstirring continued for another 15 min. To the resulting mixture wasadded HMPA (5 mL) and, after 15 min, methyl cyanoformate (30 mmol) inTHF (20 mL) and the reaction warmed to room temperature and stirredovernight. The reaction mixture was quenched with 2N HCl (50 mL). Thelayers were separated and the aqueous phase extracted with Et₂ O (1×100mL). The combined organic extracts were washed with saturated NH₄ Clsolution (3×50 mL), water (2×50 mL), brine (1×50 mL) and dried (Na₂SO₄). Removal of the solvent in vacuo and purification by eitherKugelrohr distillation or flash chromatography afforded the desiredmethyl 2-alkylcyclohexan-6-one carboxylate (Table C).

                  TABLE C                                                         ______________________________________                                        Intermediate                                                                           Alkyl     Yield   b.p.                                               ______________________________________                                        B        Me        82      --                                                 C        Et        70      100-110° C. (0.2 mm)                        D        iPr       74      106-109° C. (0.5 mm)                        ______________________________________                                    

General procedure for the preparation of methyl2-benzylthio-6-alkylcyclohex-2-ene carboxylate and2-benzylthio-6-alkylcyclohex-1-ene carboxylate: A mixture ofmethyl-2-alkylcyclohexan-6-one carboxylate (1 eq), benzylmercaptan (1.1eq) and the acidic clay montmorillonite, KSF (1.5 times the weight ofmethyl-2-alkylcyclohexan-6-one carboxylate) in anhydrous toluene (50-100mL) was refluxed under nitrogen with azeotropic removal of water for12-14 hr and cooled to room temperature. The solids were filtered offand washed with ether. The combined filtrate was washed with 10% Na₂CO₃, water, brine and dried. Removal of the solvent in vacuo andpurification of the residue by flash chromatography on silica gel (10%ether in hexanes) gave a mixture of methyl2-benzylthio-6-alkylcyclohex-2-ene carboxylate and methyl2-benzylthio-6-alkylcyclohex-1-ene carboxylate (Table D) which was usedin the next step as a mixture.

                  TABLE D                                                         ______________________________________                                        Intermediate                                                                              Alkyl   Combined Yield of Mixture                                 ______________________________________                                        A           H       40                                                        B           Me      44                                                        C           Et      50                                                        D           iPr     52                                                        ______________________________________                                    

General procedure for the preparation of 4-alkyl-tetrahydro saccharins:A solution of methyl 2-benzylthio-6-alkylcyclohex-2-ene-carboxylate andmethyl 2-benzylthio-6-alkylcyclohex-1-ene carboxylate (1-10 mmol of themixture) in 10 mL of MDC was diluted with 20-50 mL of glacial aceticacid and 1-5 mL of water, the mixture cooled to -10° C., and chlorinegas was bubbled through the mixture until the exothermic reactionsubsided. The mixture was then stirred for 10 minutes and taken todryness to give a mixture of methyl2-chlorosulfonyl-6-alkylcyclohex-2-ene carboxylate and2-chlorosulfonyl-6-alkylcyclohex-1-ene carboxylate, which was dissolvedin 10 mL of THF and added to 25 mL of a solution of concentratedammonium hydroxide while cooling in an ice/acetone bath. After stirringfor 2 hr, the reaction mixture was concentrated in vacuo, the residuetaken up in water, acidified to pH 1 with 2N HCl, and extracted withMDC. The organic phase was dried and concentrated in vacuo to give amixture of methyl 2-aminosulfonyl-6-alkylcyclohex-2-ene carboxylate and2-aminosulfonyl-6-alkylcyclohex-1-ene carboxylate. The mixture wasdissolved in methanol and added to a freshly prepared solution of sodiummethoxide (10-50 mmol) and stirred at ambient temperature for 12 hr. Thereaction mixture was concentrated in vacuo, diluted with water andextracted with ether. The organic phase was discarded, and the aqueousphase was acidified to pH 1 with concentrated HCl and extracted withMDC. The organic extracts, on washing with brine, drying and evaporationto dryness, afforded 4-alkyl.4,5,6,7-tetrahydrobenzisothiazol-3-one1,1-dioxide or 4-alkyl-tetrahydro saccharins (Table E).

                  TABLE E                                                         ______________________________________                                        Intermediates    Alkyl   Yield                                                ______________________________________                                        A                H       50                                                   B                Me      85                                                   C                Et      80                                                   D                iPr     74                                                   ______________________________________                                    

A mixture of 4-alkyl-4,5,6,7-tetrahydrobenzisothiazol-3-one 1,1-dioxide(4-alkyltetrahydro saccharin) (1.0 eq), chloromethyl phenyl sulfide (1.5eq) and tetrabutylammonium bromide (0.2 eq) in toluene (25 mL/g ofsaccharin) was refluxed under nitrogen for 16-24 hr and then cooled toroom temperature. The resulting mixture was evaporated to dryness andthe residue chromatographed on silica gel eluting with hexanes/MDC (1:1to 1:3) to give the corresponding2-phenylthiomethyl-4-alkyl-4,5,6,7-tetrahydrobenzisothiazole-3-one 1,1dioxide or 2-phenylthiomethyl-4-alkyl-tetrahydro saccharin (Table F).

                  TABLE F                                                         ______________________________________                                        Example         Alkyl   Yield                                                 ______________________________________                                        A               H       40                                                    B               Me      55                                                    C               Et      40                                                    D               iPr     53                                                    ______________________________________                                    

A solution of 2-phenylthiomethyl-4-alkyl-tetrahydro saccharin (1.0 eq)was treated with sulfuryl chloride (1.5 eq) and stirred for 2 hr. Theresulting yellow solution was taken to dryness to give2-chloromethyl-4-alkyl-tetrahydro saccharin. It is contemplated thatthis derivative can be heated with an appropriate heterocycliccarboxylic acid, anhydrous potassium carbonate and tetrabutylammoniumbromide in DMF to give the corresponding4-alkyl-4,5,6,7-tetrahydro-2-saccharinylmethyl heterocyclic carboxylate(Table G).

                  TABLE G                                                         ______________________________________                                        Example   Alkyl    Het                                                        ______________________________________                                        25A       H        3,5-Cl.sub.2 -4-pyridyl                                    25B       Me       3-CH.sub.3 -2-thienyl                                      25C       Et       3-CH.sub.3 -5-isoxozolyl                                   25D       iPr      2-oxo-5-pyrrolidinyl                                       25E       H        3,5-(CH.sub.3).sub.2 -1-phenyl-4-pyrazolyl                 25F       Me       1,3-(CH.sub.3).sub.2 -5-Cl-2-indolyl                       25G       Et       3-furanyl                                                  25H       iPr      1-CH.sub.3 -2-pyrrolyl                                     25I       iPr      2-imidazolyl                                               25J       iPr      2-CF.sub.3 -4-pyridyl                                      25K       iPr      2-CH.sub.3 O-4-pyridyl                                     25L       iPr      3,5-Cl.sub.2 -2-[2-(4-                                                        morpholinyl)ethoxyl]-4-pyridyl                             ______________________________________                                    

EXAMPLE 26

Methyl 2,2-dimethylcyclohexan-6-one carboxylate: To a suspension ofanhydrous CuI (70.0 g, 0.37 mol) in anhydrous ether (500 mL) at 0° C.was added halide-free methyl lithium (520 mL of 1.4M solution in ether,0.73 mol). After being stirred at 0° C. for 15 minutes, a solution of3-methyl-2-cyclohexenone (20.0 g, 0.18 mol) in ether (50 mL) was addedand stirring continued for another 1 hr. To the resulting mixture wasaded THF (50 mL) and HMPA (25 mL) and after 15 rain methyl cyanoformate(45.0 g, 0.53 mol) in THF (20 mL) and the reaction warmed to roomtemperature and stirred for 3 hr. The reaction mixture was quenched with2N HCl (50 mL). The layers were separated and the aqueous phaseextracted with Et₂ O (1×500 mL). The combined organic extracts werewashed with saturated NH₄ Cl solution (3×50 mL), water (2×50 mL), brine(1×50 mL) and dried (Na₂ SO₄). Removal of the solvent in vacuo andpurification by Kugelrohr distillation afforded 34.0 g (99%) of methyl2,2-dimethyl cyclohexane-6-one carboxylate, bp 80°-84° C./0.6 min.

The cyclohexanone can be converted to4,4-dimethyl-4,5,6,7-tetrahydro-2-saccharinylmethyl3,5-dichloropyridine-4-carboxylate following the procedure describedabove for Examples 25A-25L.

It should be appreciated that the methods described above would beequally applicable to the preparation of various other specific 4-R⁴ -R⁵-2-saccharinylmethyl or 4,5,6,7-tetrahydro-2-saccharinylmethylheterocyclic carboxylate derivatives. For example, treatment of anappropriate 4-R⁴ -R⁵ -2-halomethylsaccharin or4,5,6,7-tetrahydro-2-halomethylsaccharin derivative with an appropriateheterocyclic carboxylic acid derivative will produce the desired 4-R⁴-R⁵ -2-saccharinylmethyl or 4,5,6,7-tetrahydro-2-saccharinylmethylheterocyclic carboxylate derivative, which in turn can undergofunctional group transformations such as those described in Examples18A-18P to produce other 4-R⁴ -R⁵ -saccharinylmethyl or4,5,6,7-tetrahydro-2-saccharinylmethyl heterocyclic carboxylates.

BIOLOGICAL TEST RESULTS

Measurement of the inhibition constant, K_(i), of a HLE-inhibitorcomplex has been described for "truly reversible inhibition constants"usually concerning competitive inhibitors. [Cha, Biochem. Pharmacol.,24, 2177-2185 (1975)]. The compounds of the present invention, however,do not form truly reversible inhibitor complexes but are consumed by theenzyme to some extent. Thus, instead of measuring a K_(i), a K_(i) * iscalculated which is defined as the ratio of the k_(off) /k_(on), therate of reactivation of the enzyme to the rate of inactivation of theenzyme. The values of k_(off) and k_(on) are measured and K_(i) * isthen calculated.

The rate of inactivation, k_(on), of enzymatic activity was determinedfor the compounds tested by measuring the enzyme activity of an aliquotof the respective enzyme as a function of time after addition of thetest compound. By plotting the log of the enzyme activity against time,an observed rate of inactivation, k_(obs), is obtained which can berepresented as k_(obs) =1n2/t.sub. 1/2 where t.sub. 1/2 is the timerequired for the enzyme activity to drop by 50%. The rate ofinactivation is then equal to ##EQU1## where [I] is the concentration ofthe inhibiting compound.

The reactivation constant, k_(off), is similarly determined, and theinhibition constant, K_(i) *, is then calculated as

    K.sub.i *=k.sub.off /k.sub.on

The values obtained for k_(on) and K_(i) * for specific substitutedsaccharin derivatives are shown in TABLE 3, the compounds beingidentified by the Example numbers above where their preparations aredescribed.

                  TABLE 3                                                         ______________________________________                                                      K.sub.on × 10.sup.-3                                      Example       M.sup.-1 Sec.sup.-1                                                                         K.sub.i * (nM)                                    ______________________________________                                        1             1.2           40                                                2             11            10                                                3             1500          0.015                                             4             2300          0.01                                              5             455           0.022                                             6             47.6          0.21                                              7             625           0.016                                             8             100           0.10                                              9             131           0.076                                             10            63            0.16                                              11            50            0.20                                              12            28            0.36                                              13            9             1.1                                               14            500           0.02                                              15            6             1.5                                               ______________________________________                                    

We claim:
 1. A compound having the formula: ##STR19## wherein: Het is a9- or 10-membered bicyclic heterocycle containing from 1 to 2heteroatoms selected from oxygen, and nitrogen or said heterocyclessubstituted by from one to three, the same or different, members of thegroup consisting of lower-alkyl, perfluorolower-alkyl, lower-alkoxy, andhalogen;R⁴ is hydrogen, halogen, lower-alkyl, perfluorolower-alkyl,perchlorolower-alkyl, lower-alkenyl, lower-alkynyl, cyano, carboxamido,amino, lower-alkylamino, dilower-alkylamino, lower-alkoxy, benzyloxy,lower-alkoxycarbonyl, hydroxy or phenyl; and R⁵ is hydrogen or from oneto two substituents in any of the 5-, 6- or 7-positions selected fromhalogen, cyano, nitro, N═B', lower-alkyl-2-pyrrolyl,lower-alkylsulfonylamino, polyfluorolower-alkylsulfonylamino,polychlorolower-alkylsulfonylamino, aminosulfonyl, lower-alkyl,polyfluoro-lower-alkyl, polychlorolower-alkyl, cycloalkyl, lower-alkoxy,hydroxy, carboxy, carboxamido, hydroxylower-alkyl, methylenedioxy,cycloalkyloxy, formyl, aminomethyl, polyfluorolower-alkylsulfonyl,polychlorolower-alkylsulfonyl, lower-alkylsulfonylaminosulfonyl,di(lower-alkyl)phosphonoxy, lower-alkoxy-poly-lower-alkyleneoxy,hydroxy-lower-alkoxy, polyhydroxy-alkoxy, polyalkoxy-alkoxy, --SR,--SOR, --SO₂ R, --OCOR, --O--(C₁ -C₁₀ alkylene)-COOR, --O--(C₂ -C₁₀alkylene)-N═B' where R is lower-alkyl, phenyl, benzyl or naphthyl, orphenyl or naphthyl substituted by from one to two substituents selectedfrom lower-alkyl, lower-alkoxy or halogen and where N═B' is amino,lower-alkylamino, dilower-alkyl-amino, 1-azetidinyl, 1-pyrrolidinyl,1-piperidinyl, 4-morpholinyl, 1-piperazinyl,4-lower-alkyl-1-piperazinyl, 4-benzyl-1-piperazinyl, 1-imidazolyl or(carboxy-lower-alkyl)amino; or R⁵ is a 5- or 6-membered saturated ringfused to the saccharin ring at the 5,6 or 6,7 positions, said ringcontaining two heteroatoms chosen from the group consisting of nitrogen,oxygen and sulfur or a methylated derivative of said ring; oracid-addition salts of basic members thereof or base-addition salts ofacidic members thereof, with the proviso that, when R⁴ and R⁵ are bothhydrogen, Het cannot be a dihydropyridine.
 2. A compound according toclaim 1 wherein R⁴ is hydrogen, halogen, lower-alkyl or lower-alkoxy andR⁵ is hydrogen, lower-alkoxy, methylenedioxy, cycloalkyloxy,hydroxylower-alkoxy, polyhydroxy-alkoxy, polyalkoxy-alkoxy, --O--(C₁-C₁₀ alkylene)-COOR, or --O--(C₂ -C₁₀ alkylene)-N═B'.
 3. A compoundaccording to claim 1 wherein Het is a 9- or 10-membered bicyclicheterocycle containing from 1 to 2 heteroatoms selected from oxygen, andnitrogen or said heterocycles substituted by from one to three, the sameor different, members of the group consisting of lower-alkyl,perfluorolower-alkyl, lower-alkoxy, and halogen.
 4. A compound accordingto claim 3 wherein Het is indolyl or indolyl substituted by one or two,the same or different, members of the group consisting of lower-alkyl,perfluorolower-alkyl, lower-alkoxy, and halogen. 5.[4-Isopropyl-6-methoxy-3-oxo-1,2-benzisothiazol-2(3H)-yl]methyl1,3-dimethyl-5-chloroindole-2-carboxylate according to claim
 4. 6. Acomposition for the treatment of degenerative diseases which comprises apharmaceutical carrier and an effective proteolytic enzyme-inhibitingamount of a compound having the formula: ##STR20## wherein: Het is a 9-or 10-membered bicyclic heterocycle containing from 1 to 2 heteroatomsselected from oxygen, and nitrogen or said heterocycles substituted byfrom one to three, the same or different, members of the groupconsisting of lower-alkyl, perfluorolower-alkyl, lower-alkoxy, andhalogen;R⁴ is hydrogen, halogen, lower-alkyl, perfluorolower-alkyl,perchlorolower-alkyl, lower-alkenyl, lower-alkynyl, cyano, carboxamido,amino, lower-alkylamino, dilower-alkylamino, lower-alkoxy, benzyloxy,lower-alkoxycarbonyl, hydroxy or phenyl; and R⁵ is hydrogen or from oneto two substituents in any of the 5-, 6- or 7-positions selected fromhalogen, cyano, nitro, N═B', lower-alkyl-2-pyrrolyl,lower-alkylsulfonylamino, polyfluorolower-alkylsulfonylamino,polychlorolower-alkylsulfonylamino, aminosulfonyl, lower-alkyl,polyfluoro-lower-alkyl, polychlorolower-alkyl, cycloalkyl, lower-alkoxy,hydroxy, carboxy, carboxamido, hydroxylower-alkyl, methylenedioxy,cycloalkyloxy, formyl, aminomethyl, polyfluorolower-alkylsulfonyl,polychlorolower-alkylsulfonyl, lower-alkylsulfonylaminosulfonyl,di(lower-alkyl)phosphonoxy, lower-alkoxy-poly-lower-alkyleneoxy,hydroxy-lower-alkoxy, polyhydroxy-alkoxy, polyalkoxy-alkoxy, --SR,--SOR, --SO₂ R, --OCOR, --O--(C₁ -C₁₀ alkylene)-COOR, --O--(C₂ 1∝C₁₀alkylene)-N═B' where R is lower-alkyl, phenyl, benzyl or naphthyl, orphenyl or naphthyl substituted by from one to two substituents selectedfrom lower-alkyl, lower-alkoxy or halogen and where N═B' is amino,lower-alkylamino, dilower-alkyl-amino, 1-azetidinyl, 1-pyrrolidinyl,1-piperidinyl, 4-morpholinyl, 1-piperazinyl,4-lower-alkyl-1-piperazinyl, 4-benzyl-1-piperazinyl, 1-imidazolyl or(carboxy-lower-alkyl)amino; or R⁵ is a 5- or 6-membered saturated ringfused to the saccharin ring at the 5,6 or 6,7 positions, said ringcontaining two heteroatoms chosen from the group consisting of nitrogen,oxygen and sulfur or a methylated derivative of said ring; oracid-addition salts of basic members thereof or base-addition salts ofacidic members thereof.
 7. A composition according to claim 6 wherein R⁴is hydrogen, halogen, lower-alkyl or lower-alkoxy and R⁵ is hydrogen,lower-alkoxy, methylendioxy, cycloalkyloxy, hydroxylower-alkoxy,polyhydroxy-alkoxy polyalkoxy-alkoxy, --O--(C₁ -C₁₀ alkylene) --COOR; or--O--(C₂ -C₁₀ alkylene)-N═B'.
 8. A method for the treatment ofdegenerative diseases which comprises administering to a patient in needof such treatment a medicament containing an effective proteolyticenzyme-inhibiting amount of a compound having the formula: ##STR21##wherein: Het is a 5-membered monocyclic heterocycle or a 9- or10-membered bicyclic heterocycle containing from 1 to 2 heteroatomsselected from oxygen, and nitrogen or said heterocycles substituted byfrom one to three, the same or different, members of the groupconsisting of lower-alkyl, perfluorolower-alkyl, lower-alkoxy, andhalogen;R⁴ is hydrogen, halogen, lower-alkyl, perfluorolower-alkyl,perchlorolower-alkyl, lower-alkenyl, lower-alkynyl, cyano, carboxamido,amino, lower-alkylamino, dilower-alkylamino, lower-alkoxy, benzyloxy,lower-alkoxycarbonyl, hydroxy or phenyl; and R⁵ is hydrogen or from oneto two substituents in any of the 5-, 6- or 7-positions selected fromhalogen, cyano, nitro, N═B', lower-alkyl-2-pyrrolyl,lower-alkylsulfonylamino, polyfluorolower-alkylsulfonylamino,polychlorolower-alkylsulfonylamino, aminosulfonyl, lower-alkyl,polyfluoro-lower-alkyl, polychlorolower-alkyl, cycloalkyl, lower-alkoxy,hydroxy, carboxy, carboxamido, hydroxylower-alkyl, methylenedioxy,cycloalkyloxy, formyl, aminomethyl, polyfluorolower-alkylsulfonyl,polychlorolower-alkylsulfonyl, lower-alkylsulfonylaminosulfonyl,di(lower-alkyl)phosphonoxy, lower-alkoxy-poly-lower-alkyleneoxy,hydroxy-lower-alkoxy, polyhydroxy-alkoxy, polyalkoxy-alkoxy, --SR,--SOR, --SO₂ R, --OCOR, --O--(C₁ -C₁₀ alkylene) --COOR, --O--(C₂ -C₁₀alkylene)-N═B' where R is lower-alkyl, phenyl, benzyl or naphthyl, orphenyl or naphthyl substituted by from one to two substituents selectedfrom lower-alkyl, lower-alkoxy or halogen and where N═B' is amino,lower-alkylamino, dilower-alkyl-amino, 1-azetidinyl, 1-pyrrolidinyl,1-piperidinyl, 4-morpholinyl, 1-piperazinyl,4-lower-alkyl-1-piperazinyl, 4-benzyl-1-piperazinyl, 1-imidazolyl or(carboxy-lower-alkyl)amino; or R⁵ is a 5- or 6-membered saturated ringfused to the saccharin ring at the 5,6 or 6,7 positions, said ringcontaining two heteroatoms chosen from the group consisting of nitrogen,oxygen and sulfur or a methylated derivative of said ring; oracid-addition salts of basic members thereof or base-addition salts ofacidic members thereof.
 9. A method according to claim 8 wherein R⁴ ishydrogen, halogen, lower-alkyl or lower-alkoxy and R⁵ is hydrogen,lower-alkoxy, methylenedioxy, cycloalkyloxy, hydroxylower-alkoxy,polyhydroxy-alkoxy polyalkoxy-alkoxy, --O--(C₁ -C₁₀ alkylene) --COOR, or--O--(C₂ 1∝C₁₀ alkylene)-N═B'.